Next Article in Journal
Dieckol and Its Derivatives as Potential Inhibitors of SARS-CoV-2 Spike Protein (UK Strain: VUI 202012/01): A Computational Study
Next Article in Special Issue
Bridging Cyanobacteria to Neurodegenerative Diseases: A New Potential Source of Bioactive Compounds against Alzheimer’s Disease
Previous Article in Journal
Sulfated and Sulfur-Containing Steroids and Their Pharmacological Profile
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications

1
Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
2
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Kom 32512, Egypt
3
Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
4
Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Straße 2, 12489 Berlin, Germany
5
Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz 71348-53734, Iran
6
School of Computing, Engineering & Physical Sciences, University of the West of Scotland, High Street, Paisley PA1 2BE, UK
7
School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
8
Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
9
Laboratory of Medicinal Plant Biotechnology, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 311402, China
10
National Institute of Oceanography & Fisheries, NIOF, Cairo 11516, Egypt
11
Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, China
12
School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
13
International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
14
Pharmacognosy Group, Department of Pharmaceutical Biosciences, Uppsala University, Biomedical Centre, P.O. Box 574, SE-751 23 Uppsala, Sweden
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2021, 19(5), 241; https://doi.org/10.3390/md19050241
Submission received: 23 February 2021 / Revised: 25 March 2021 / Accepted: 15 April 2021 / Published: 24 April 2021

Abstract

:
Cyanobacteria are photosynthetic prokaryotic organisms which represent a significant source of novel, bioactive, secondary metabolites, and they are also considered an abundant source of bioactive compounds/drugs, such as dolastatin, cryptophycin 1, curacin toyocamycin, phytoalexin, cyanovirin-N and phycocyanin. Some of these compounds have displayed promising results in successful Phase I, II, III and IV clinical trials. Additionally, the cyanobacterial compounds applied to medical research have demonstrated an exciting future with great potential to be developed into new medicines. Most of these compounds have exhibited strong pharmacological activities, including neurotoxicity, cytotoxicity and antiviral activity against HCMV, HSV-1, HHV-6 and HIV-1, so these metabolites could be promising candidates for COVID-19 treatment. Therefore, the effective large-scale production of natural marine products through synthesis is important for resolving the existing issues associated with chemical isolation, including small yields, and may be necessary to better investigate their biological activities. Herein, we highlight the total synthesized and stereochemical determinations of the cyanobacterial bioactive compounds. Furthermore, this review primarily focuses on the biotechnological applications of cyanobacteria, including applications as cosmetics, food supplements, and the nanobiotechnological applications of cyanobacterial bioactive compounds in potential medicinal applications for various human diseases are discussed.

1. Introduction

Cyanobacteria, whose metabolism has played a unique role in ecosystems since ancient times, have probably been in existence for more the 3.5 billion years [1]. Cyanobacteria, previously known as blue-green algae, are the most primitive organism present on the earth. They play a vital role as the primary sources of oxygen and as nitrogen fixing agents in aquatic environments [2]. Indeed, the oxygen fixing properties of these organisms made life on Earth possible billions of years ago. Cyanobacteria are found in different habitats, from fresh water lakes, ponds to maritime coasts and the open ocean, occupying the largest ecosystem in the planet. The aquatic cyanobacteria are divided into two large ecological groups: planktonic cyanobacteria, which float freely in the water column, and benthic cyanobacteria, which adhere to submerged solid surfaces (i.e., sediments, rocks, stones, algae, and aquatic plants) [3]. For example, the planktonic cyanobacteria species Prochlorococcus and Synechococcus are prevalent in many oceans [4]; additionally, C theyanobium and Synechocystis genera are vastly distributed in marine planktonic collections [5]. Some researchers believe that the “Red Sea” has its name because of the dense population of Trichodesmium erythraeum (sea sawdust), which is mostly present there. In tropical seas with surface temperatures above 25 °C and saltiness up to 35%, Trichodesmium sp. occurs. Trichosdesmium is a filamentous nonheterocystous cyanobacterium, that fixes air N2 [6]. Microcystis, Cylindrospermopsis, Anabaena and Aphanizomenon are the common genera that flourish. Their environmental vulnerability and short life cycles leading to the rapid turnover of organisms promote their use as biological indicators for environmental studies [7]. For example, N2 cyanobacterial fixing was used to understand the quality of water with extremely high turbidity, the low N: P ratio, the toxicity of metals and the environmental limits of nitrogen. Some of these organisms and symbiotic systems like Azolla, particularly for rice production, are used as biofertilizer [8]. They are also used in oxidation ponds and in treating plants for waste and sludge [9]. Recently, a few species were investigated for the development of biofuel after they were found to be the most effective of all living organisms in converting solar energy. In addition, their simple genomic structure has allowed genetic engineering to produce biofuel strains [10]. Cyanobacteria also interact with limestone; one of the more intriguing aspects is the capacity of some strains (euendoliths) to penetrate directly into the carbonate substrate. Inhibition and gene expression analysis using the Mastigocoleus BC008 have shown that the uptake and transport of Ca2+ is guided by a sophisticated mechanism unrivaled between the bacteria, P-style Ca2+ ATPases [11]. There is much evidence to be found that endolithic stigma products such as Brachytrichia and Mastigocoleus derive nutrients from the surrounding rock or from the outside [12]. Symbioses occur between cyanobacteria and other marine organisms such as sponges, ascidians, lichens, dinoflagellates, euchiuroid worms and macroalgae. They act as nitrogen fixing agents and releasers of dissolved organic carbon that benefit their hosts, also producing defensive specialized metabolites that save their hosts from being attacked by predators. One of the major host organisms for cyanobacteria are sponges. The most abundant bacterial phylum found in the different sponges of the Persian Gulf were cyanobacteria, constituting more than 44% of their total phylum diversity [13]. This indicates an important ecological interaction between the cyanobacteria and sponges [14,15]. Lichens are symbiotic associations between fungi and photosynthetic algae or cyanobacteria. Microcystins are potent toxins associated with aquatic cyanobacterial blooms that are responsible for the poisoning of both humans and animals [16].
Around 450 compounds from marine cyanobacteria were identified, particularly from the genera Lyngbya, Oscillatoria, and Symploca. Around 58% of the cyanobacterial metabolites were derived from Oscillatoria, while 35% of these natural products belonged to Lyngbya [17]. They importantly produce a broad variety of bioactive compounds, including toxin metabolites with potential anticancer properties, and produce promising results for future research into the regulation of human carcinoma [18]. For example, apratoxin D, was isolated from Lyngbya sp., has strong cytotoxicity against human lung cancer cells [19]. Additionally, symplocamide A was isolated from the marine cyanobacterium Symploca sp. and has shown powerful cytotoxicity to neuroblastoma cells and lung cancer cells [20]. For instance, Kurisawa et al. [21] isolated three new linear peptides from Dapis sp. Furthermore, cyanobacteria have long been known to produce the most efficient chemical defense specialized metabolites from different classes of natural products such as lipopeptides, alkaloids, depsipeptides, macrolides/lactones, peptides, terpenes, polysaccharides, lipids, polyketides [22]. For doing so, they used plenty of enzymes, specialized for the biosynthesis of their basic skeletons and also tailoring enzymes for their modification [23]. The majority of cyanobacterial activity is essentially related to their lipopeptide content [24,25,26].
Marine cyanobacteria with various and adverse chemical products have attracted the attention of many scientists from different fields, in particular medicinal chemistry and pharmacology [27]. They possess significant biological properties including antibacterial, antifungal, anticancer, antituberculosis, immunosuppressive, anti-inflammatory, and antioxidant properties [28,29,30]. Cyanobacteria are rich in omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are known to prevent inflammatory cardiovascular diseases [31]. Many studies have shown that cyanobacteria produce compounds with increased pharmaceutical and biotechnological interest and have applications in human health with numerous biological activities and as a dietary supplement [32]. Polyhydroxyalkanoates (PHAs) are polyesters produced by many cyanobacterial strains, which can be used as a substitute for nonbiodegradable plastics. Most studies have shown that oil-polluted sites are rich in cyanobacterial consortia capable of degrading oil components by providing the associated oil-degrading bacteria with the necessary oxygen, organic matter and fixed nitrogen [33]. However, cyanobacterial hydrogen was regarded as a promising alternative energy source which is now available on the market [34]. In addition to these applications, cyanobacteria are also used as food, fertilizers [35], wastewater treatment, aquaculture, a source of pharmacologically important secondary metabolites [33]. Nanobiotechnological applications of marine cyanobacterial metabolites that have biomedical applications may provide a novel method to overcome the poor water solubility of hydrophobic marine natural drugs and use cyanobacteria for industrial and medicinal purposes [36]. Nanomedicine has made significant advances in the use of nanocarrier formulations to deliver therapeutic drugs and diagnostic agents to tumor/cancer sites [37]. The use of marine cyanobacteria in cosmetics, cosmeceutical formulations and thalassotherapy due to its bioactive components possesses many advantages, including the maintenance of skin structure and function, which have gained interest as a concern for modern societies. It is also linked to its ability to regenerate and protect itself against external environmental conditions [38,39]. Cyanobacteria could be incorporated into the health and wellness treatments used in thalassotherapy centers due to their high concentration of biologically active substances [40]. This review presents an overview focusing on the biotechnological applications, therapeutic properties and clinical uses of cyanobacteria and their metabolites in addition to introducing their synthetic bioactive compounds.

2. Preclinical and Clinical Trials of Metabolites from Marine Cyanobacteria

The vital role of different metabolites from marine cyanobacteria as therapeutic agents is described and classified in two groups; preclinical and clinical entities. Those compounds (141, 43 and 44) that are involved in preclinical trials are illustrated in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5 and Figure 6. These bioactive compounds have well-known anti-inflammatory and anticancer properties and are used as external enzymes and antibiotics [41,42,43,44]. Those that are clinically validated, i.e., from compound 42, 4559, are also mentioned in Figure 7. The different cyanobacteria species from which these metabolites have been reported and the related biological activities are discussed briefly.

2.1. Bioactive Constituents of Marine Cyanobacteria

2.1.1. Antioxidant and Antiobesity Supplements from Cyanobacteria

Photosynthetic organisms such as cyanobacteria have developed many strategies to prevent the harmful effects of reactive oxygen species. Increased catalase and superoxide dismutase activity was necessary to regulate metal oxidative stress [45]. Scytonemin (SCY, 1), a dimeric indole alkaloid which is therapeutic to the disorders of proliferation and inflammation, was isolated from Lyngbya arboricola, Nostoc commune, Scytonema geitleri [46]. Rivularia [47], and Calothrix sp. [48] showed strong antioxidant activity and averts up to 90% of solar UV radiation from entering the cell [49,50,51,52]. Cell safety can be provided by the enhancement of the antioxidant status and the elimination of superoxide anions and other oxygen derivatives [53,54]. In addition, antioxidant activity was reported from the methanolic extracts of Synechocystis sp., Leptolyngbya sp. and Oscillatoria sp. [55], and ethanolic extracts of Nostoc sp., Anabaena sp., Calothrix sp., Oscillatoria sp. and Phormidium sp. [56].
Phycocyanobilin (2) is tetraspyrole chromophore of blue green algae (Spirulina) which responsible for the blue color of Spirulina—in spite of that fact that it has almost the same structure as bilirubin, the pigment is more soluble than bilirubin, and 2 was reported to have proven health-promoting activities as an efficient quencher of different oxygen derivatives, and so possessed high antioxidant potential, protecting the live cell from extreme oxidative stress [57]. Spirulina is a cyanobacterium that can be used up orally, i.e., without any processing and is very useful to human health including enhancement of the immune system activity, antioxidant, anticancer, and antiviral effect. Thus, Spirulina is able to regulate hyperlipidemia and cholesterol levels and provide cell defense against a range of conditions including allergies, asthma, diabetes, hepatotoxicity, immunomodulation, inflammation and obesity [58,59].
Several clinical and preclinical trials have been conducted to test the benefits of Spirulina sp. on weight loss with promising results. Polyphenols are powerful antioxidants and natural products that may help reduce body weight. Miranda et al. [60] claimed that the main phenolic compounds—namely, chlorogenic acid, synaptic acid, salicylic acid, transcinnamic acid, and caffeic acid—were commonly present in Spirulina. The DPPH assay and hydroxyl scavenging assay done by Al-Dhabi and Valan Arasu [61], revealed that all the Spirulina extracts showed the activity in a concentration-dependent manner.
Yousefi et al. [62] studied 52 obese participants with a body mass index (BMI) > 25–40 kg/m2. They divided the candidates randomly into two different groups, namely, treated and placebo groups; the first group took Spirulina tablets (SP), 500 mg along with restricted calorie diet (RCD) 4 times a day, while the second group were given placebo tablets and RCD with the same daily regime for the 12 weeks of the intervention. Medical measurements, appetite scores and biochemical assessments were performed at the beginning, 6 and 12 weeks. Body weight, fat and BMI, together with waist dimension and appetite scores, were significantly reduced in the SP treated candidates compared to those measured in the placebo group.
Many pigments, such as carotenes, xanthophylls and chlorophylls, were identified using Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR-MS), which was used to elucidate the qualitative profile of Spirulina (Arthrospira platensis). β-carotene, two xanthophylls (diatoxanthin (3) and diadinoxanthin (4)) showed the highest scavenging activity using precolumn reaction with DPPH radical followed by rapid UHPLC-PDA separation (Figure 1) [63].

2.1.2. Cytotoxic Agents from Cyanobacteria

The peptolide cryptophycin (5), which was isolated from Nostoc sp., showed cytotoxic properties [64]. However, in other findings, the polyketide borophycin (6) from Nostoc linckia and Nostoc spongiaeforme showed antitumor activity against LoVo (MIC 0.066 µg/mL) and KB (MIC 3.3 µg/mL) [65,66]. Three new linear peptides (iheyamides A (7), B (8), and C (9)) were isolated from Dapis sp. (Figure 2). The new compounds were evaluated for cytotoxicity using normal human cells (WI-38), and antitrypanosomal activity against (Trypanosoma brucei rhodesiense and Trypanosoma brucei brucei) as models, respectively. The findings showed that compound 7 has potent antitrypanosomal and cytotoxic activity with IC50 values of 1.5 and 18 µM, respectively, compared with pentamide as a positive control with IC50 ranging between 0.001 to 0.005 µM. While compounds 8 and 9 had low activity with IC50 > 20 µM, the acting mechanism of 7 involved its growth-inhibitory activity against T. b. rhodesiense and T. b. brucei. Finally, the result indicates that compound 7 is a promising lead compound for a new drug [21].
Furthermore, Yu et al. [25] isolated nine new linear lipopeptides, microcolins E–M (1018), from the marine cyanobacterium Moorea producens, which exhibited significant cytotoxic activity against lung carcinoma using MTT assay (Figure 3). Malyngamides are isolated amides of marine cyanobacteria. Lyngbya majuscula-producing malyngamide C (19) and 8-O-acetyl-8-epi-malyngamide C (20) have exhibited cytotoxicity against colon cancer cells HT29, with IC50 values 5.2 and 15.4 µM, respectively [67]. Additionally, they have antiproliferating effects against a variety of cancer cell lines, for example, heLa cell lines with EC50 (µM) 0.12 ± 0.01 and 0.24 ± 0.0, respectively [68]. Hierridin B (21) is a polyketide produced by Cyanobium sp. and has a selective cytotoxicity against colon cancer cell line HT-29 with an IC50 value of 0.1 µM [69]. Furthermore, apratoxins are cyclic depsipeptides isolated from marine cyanobacteria that inhibit several cancer cells lines at nanomolar concentration. Apratoxin A (22) produced by Lyngbya boulloni has been shown to be cytotoxic against adenocarcinoma cells [70]. Coibamide A (23) was isolated from Leptolyngbya sp. [71] and exhibited cytotoxicity against NCIH460 lung and mouse neuro-2a cells [72]. Tasipeptins A–B (24) and (25) are depsipeptides isolated from Symploca sp. that showed cytotoxic activity against KB cells with IC50 values of 0.93 and 0.82 µM, respectively [73]. Desmethoxymajusculamide C (26), DMMC is a cyclic depsipeptide from Lyngbya majuscule and showed potent cytotoxicity in both cyclic and ring-opened structural forms. Both of them showed cytotoxic activity against HCT-116 human colon carcinoma, H-460 human large cell lung carcinoma, MDA-MB-435 human carcinoma, neuro-2A murine neuroblastoma (Figure 4) [74].

2.1.3. Antiparasite Agents

The bioactive linear alkynoic lipopeptides; carmabin A (27), dragomabin (28), dragonamide A (29) and dragonamide B (30) have been isolated from a Panamanian strain of the marine cyanobacterium Lyngbya majuscula. Good antimalarial activities of IC50 4.3, 6.0, and 7.7 µM, were reported for the first three compounds, respectively, while the later 30 was inactive. Unlike its antimalarial effect, compound 30 exhibited the best cytoxicity against Vero cells (IC50 = 9.8 µM) among mammalian cells and parasites compared to that for 28 or 29 with IC50s = 182.3 µM and 67.8 µM, respectively [75]. Dragonamides C (31) and D (32), were isolated from Lyngbya polychroa [42], dragonamide E (33) from L. majuscula that was found to be active against leishmaniasis. Compound 29 and 33 exhibited strong antileishmanial activity with IC50 values of 6.5, 5.1, and 5.9 µM, respectively [76].
In 2010, Sanchez et al. [77] isolated and identified a series of cytotoxic lipopeptides from L. majuscule, namely almiramids A–C (34, 35, and 36), that revealed strong in vitro antiparasitic activity against genus leishmania, principally L. donovani, L. infantum, and L. chagasi. The lipopeptide mabuniamide (37) was isolated from Okeania sp. The evaluation of the antimalarial activity was conducted on Plasmodium falciparum 3D7 clone in in vitro. The results reported that 37 exhibits a potent effect with IC50 of 1.4 ± 0.2 µM when compared with positive control chloroquine (IC50 7.6 ± 0.5 nM). This study records a flaw by not reporting the mode of action for the evaluated compound [26]. Calothrixins A (38) and B (39), as natural quinone products developed by Calothrix cyanobacteria, have also been shown to possess potent activity against malaria parasites; IC50 values were 58 ± 8 s.d. nM and 180 ± 44 s.d. nM, respectively, against Plasmodium falciparum [78] (Figure 5).

2.1.4. Antiviral Natural Products with Anti-SARS-CoV-2 Potential from Cyanobacteria

Calcium spirulan (Ca-SP), a sulfated polysaccharide was isolated from Arthrospira platensis, is a promising candidate for the development of broad-spectrum antiviral drugs with novel modes of action. Ca-SP was found to be composed of rhamnose, 3-O-methylrhamnose (acofriose), 2,3-di-O-methylrhamnose, 3-O-methylxylose, sulfate, and uronic acids [79]. Ca-SP displays a broad-spectrum antiviral activity which was characterized by strong inhibition of in vitro replication of human viruses such as HCMV, HSV-1, HHV-6 and HIV-1 [80]. Polysaccharides possess significant antifibrotic properties in the pulmonary tissues and are considered beneficial against human coronavirus diseases. The polysaccharides derived from different species of Spirulina and especially Spirulina platensis were found to exhibit distinct antiviral activity against different enveloped viruses [81]. Hayashi et al. [80,81] evaluated the antiviral potential of calcium-spirulan derived from Spirulina platensis against HIV-1 and HSV-1 in comparison with the standard dextran sulfate. The serum samples of the mouse models administrated with calcium-spirulan showed long-lasting antiviral activity after 24 h of administration); however, their role in COVID-19 (SARS-CoV2 infections) remains limited [82]. The isolation of the antiviral polysaccharide nostoflan from a Terrestrial Cyanobacterium and Nostoc flagelliforme was another promising discovery, as it has potent antiherpes simplex virus type 1 (HSV-1) activity with a selectivity index (50% cytotoxic concentration/50% inhibitory concentration against viral replication) [83]. Using molecular docking and MD simulation studies, cyanovirin-N (40) was the highest among other lectins and was characterized with glycan type of S glycoprotein of SARS-CoV-2. Lokhande et al. [84] showed that BanLec wild-type and its mutant form have more thermodynamically stable binding complexes with SARS-CoV-2 S glycoprotein. By using in silico molecular docking and in vitro enzymatic assay screenings, it was found that 2 is a potent phytochemical inhibitor to SARS-CoV-2 Mpro and PLpro proteases. Compound 2 demonstrated IC50 values of 71 and 62 μM for SARS-CoV-2 Mpro and PLpro, respectively. Further docking studies on compound 2 with other CoVsMpro and PLpro proteases revealed its broad-spectrum inhibition activity [85]. Naidoo et al. [86] examined 23 cyanobacterial metabolites against the SARS-CoV-2 Mpro and PLpro proteases that were proved effective, i.e., antillatoxin (41), 38, curacin A (42), 5, cryptophycin 52 (43) and 22. Compounds 22 and 43 showed superior inhibitory potential against SARS-CoV-2 Mpro based on the binding energy scores of the interactions. Compounds 5 and 43 displayed significant inhibitory prospects against the PLpro of SARS-CoV-2 (Figure 6).

2.2. Clinical Trials of Metabolites from Marine Cyanobacteria

Focusing on marine biotechnology, more than 300 nitrogen-containing secondary compounds have been reported from the prokaryotic marine cyanobacteria [22]. Most of these metabolites are biologically active and are either nonribosomal (NRP) or derived from mixed polyketide-NRP biosynthetic pathways. NRP biomolecules and structural types of hybrid polyketides-NRPs are important components of natural products used as therapeutic agents. These include vancomycin, cyclosporine and bleomycin as antibiotics, immunosuppressive and anticancer agents [87]. Crude cyanobacterial extract screening has reported the effectiveness of identifying profitable compounds and been applied to clinical trials phases [88]. For example, the methanolic extracts of Oscillatoria acuminata, Oscillatoria amphigranulata and Spirulina platensis showed strong activity such as cytotoxicity, antioxidant and antimicrobial activity [89]. A remarkable drug discovery effort is made by the diversity of unique classes of marine cyanobacteria natural products [90]. Some of the marine cyanobacterial compounds and their analogs have shown exciting results and were successfully used in the clinical trials as shown in Table 1 (Preclinical, Phase I, Phase II, Phase III and IV), such as dolastatin 10 (44), dolastatin 15 (45), 43, soblidotin (46), cemadotin (47), tasidotin (48), synthadotin (49), curacin (50) [91], anatoxin-a (51), bacteriocins, toyocamycin (52), phytoalexin (53), 40 and phycocyanin (54), and as various potential drug candidates for drug discovery. Their structures were exhibited in Figure 7, while their occurrences and bioactivities were reported in Table 1.
Compounds 44 and 45 have exhibited promising results in phase II clinical trials for cancer treatments, while compounds 47, 48 and 49, as synthetic analogs of compound 45, showed promising results in phase II clinical trials, as described in Table 1. Additionally, the synthetic analog 43, which was applied to Phase III clinical trials to treat hypertension metabolic disorder, was derived from 5. Compound 46, a synthetic analog of compound, exhibited promising results in phase II clinical trials for sarcoma, melanoma and lung cancer treatment [92,101]. Compound 51 is a toxin isolated from blooms of the cyanobacterium Anabaena circinalis that is known for its worldwide production of a range of toxins [122]. The water samples were collected from east to west side of Zemborzycki reservoir, the samples were fixed with NaN3 and extracted by ultrasonication on ice in 75% methanol acidified with 2 M HCl. The tested scum extract was highly toxic when tested against the ciliate Tetrahymena thermophile. A complete growth inhibition was observed after 24 h of incubation with undiluted extract and the diluted ones that contain ≥ 258.90 µg/L of anatoxin-a [123].
Compound 40 is a 11-kDa virucidal protein isolated from the cultures of Nostoc ellipsosporum [124]. Filtration, freeze drying and extraction by MeOH-CH2Cl2 (1:1) followed by H2O were carried out to harvest the unialgal strain of the N. ellipsosporum cellular mass [125]. Buffa et al. [126] reported that compound 40 as a potent HIV type 1 inhibitor. The virus causes infection in cervical explant models with an IC90 of 1 mM. Dendritic cells were seen migrated out of the tissue explant and the secondary virus dissemination was inhibited by 70% when using the above described concentration.
Compound 52 and its derivatives are majorly responsible for the cytotoxicity and antifungal activity of the blue-green algae belonging to the scytonemataceae. Compound 52 was first isolated from streptomyces tubercidicus and streptomyces toyocaensis, respectively [127]. Compound 52 also was prescribed to induce a growth inhibition in pancreatic cancer cell lines by inhibiting the unfolded protein response, and also by the inhibition of both P-TEFb and PKC [128,129].
Bacteriocin is a genome mining study which proved the widespread of gene clusters encoding bacteriocins in cyanobacteria viz., Prochlorcoccus marinus, Synechococcus sp., Cyanothece sp., Microcystis aeruginosa, Synechocystis sp., Arthospira sp., Nostoc sp., Anabaena sp., Nodularia sp. [116,130]. Bacteriocins are defined as ribosomally synthesized proteinaceous compounds that are lethal to bacteria [131], in vivo activity following an intravenous regimen against pathogens, i.e., nisin has been shown to be 8–16 times more active than vancomycin in targeting Streptococcus pneumoniae. Equally important, nisin F, the naturally known nisin variant, was proved effective in stopping the pathogen growth in the respiratory system and the peritoneal cavity of the rat model, similarly suppressing the growth of Staphylococcus aureus in vivo when applied within bone cement [132].
Compound 54 extraction was evaluated using different solvents, including 10 mM sodium acetate buffer (pH 5.0), NaCl 0.15 M, 10 mM sodium phosphate buffer (pH 7.0), distilled water, and CaCl2 10 g L−1. We mixed 2 g of dried biomass with 50 mL of the solvent and it then was subjected to shaking at 30 °C and extraction.
Spirulina is a blue-green alga that was used by NASA as a dietary supplement in space for astronauts. It has been reported that Spirulina exhibits anti-inflammatory properties by inhibiting the release of histamine from mast cells [133]. Ishii et al. [133] also studied the influence of Spirulina on IgA levels in human saliva and suggested a pivotal role of microalga in mucosal immunity.
Phytoalexin, resveratrol (53 is a stilbene compound; transresveratrol is synthesized in Synechocystis sp. PCC 6803 [134]. Resveratrol intake enhanced the release of the insulin-dependent glucose transporter, GLUT4, in rats with streptozotocin-induced diabetes and stimulated the insulin sensitivity mediated by the increase of adiponectin levels.
Furthermore, resveratrol induces the secretion of the gut incretin hormone glucagonlike peptide-1, as well as activating Sir2 (silent information regulatory 2) [135]. Furthermore, a phase II study of glembatumumab vedotin (GV) showed peptide for its active efficacy in the treatment of breast cancer and melanoma at a maximum tolerable dose of 1.0–1.88 mg/kg [136]. Brentuximab vedotin 63 (Adcetris™) (Adcetris as a trade name), peptide drug isolated from Symploca hydnoides and Lyngbya majuscule was approved by U.S. Food and Drug Administration (FDA) and European Medicines Evaluation Agency (EMEA) for cancer treatment [137].

3. Applications of Cyanobacteria in Biotechnology

Cyanobacteria are arguably the most important group of microorganisms on the Earth. They are one of the early settlers of the barren parts of many oceanic regions [138]. Cyanobacteria fulfill vital ecological functions in the world’s oceans, being important contributors to global carbon and nitrogen budgets [139]. Recently significant attention has been paid to the application of marine cyanobacteria in the biotechnology field [92,140]. Due to their large range of industrial applications, they have been the focal point of many recent studies: biofuels, coloring dyes, food additives, and biofertilizers [141]. In addition, they are used in production of bioplastics, water treatment [33], hydrogen production [142], cosmetics [40], forestry, animal feed [143], and application in nanobiotechnology [36], as illustrated in Figure 8. Bioethanol, biodiesel, biohydrogen, and biogas are the highly in demand as energy sources [144]. Furthermore, the comparative yields of the biofuels produced by cyanobacteria and microalgae and other natural sources were reported [145]. The productivity of cyanobacteria and microalgae was 60,548 compared to palm seed, castor, sunflower, rape seed, soybean and the corn (the least productive source) with productivity of 4747, 1156, 946, 862, 321 and 152 (kg/ha year), respectively. The abovementioned information suggested the importance of the applications of cyanobacteria in biotechnology.

3.1. NanoBiotechnological Use of Cyanobacterial Extracts and Metabolites

Nanoscience and nanotechnology have now become a modern discipline with a wide variety of applications for fundamental science. Nanotechnology plays a major role in multilayer trends, particularly in the health and life sciences, with a focus on ecofriendly new techniques [146]. Nanotechnology can encourage a new way to prevent hydrophobial, naturally occurring marine medicines with low water solubility [147] using various microorganisms, including simple bacteria and highly complex eukaryotes [148]. Nanotechnology is one of the fastest medical and industrial platforms [36] which could be implemented using desirable methods which improve stability, bioavailability and solubility [149]. Metallurgies, polysaccharides, lipids, peptide-based nanoformulations that play important role in medical diagnosis, drug delivery systems, antisense and gene therapies and tissue engineering, are healthy and ecofriendly nanomaterials [150,151]. In the fields of antimicrobial activity, wound care, medication transmission, the transmission of genes, cancer therapy and tissue engineering, polysaccharide-dependent nanoparticles are important components [152,153]. Marine cyanobacteria have many applications in nanobiotechnology, either through their direct use in the production of nanoparticles of different metals or through the nanotechnological processing of their bioactive metabolites in medicine as shown in Figure 9.
Several cyanobacterial species such as Anabaena sp., Lyngbya sp., Synechococcus sp., Synechocystis sp., Cylindrospermopsis sp., Oscillatoria willei and Pectonema boryanum were incorporated in the production of silver nanoparticles (NPs) by adding AgNO3 into a cell-free culture liquid prior to the cyanobacteria live and washed biomass suspension [154,155,156]. Cyanobacteria of the genera Anabaena, Calothrix and Leptolyngbya are also used to modify the shape of nanoparticles of gold, silver, palladium and platinum [157]. Such metal nanoparticles possess antimicrobial effects against many bacteria, including Bacillus megatarium, Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, and Micrococcus luteus [155]. In many areas, silver nanoparticles are also important, particularly in cosmetics and impregnating medical devices such as surgical masks and implantable devices with considerable antimicrobial effectiveness [158]. Encapsulation is by several coatings including external silicon layers of the cyanobacterial strain (Synechococcus sp.) [159].
Nanoformulated antiaging, antioxidants and anti-inflammatory creams or medicines have been developed with cyanobacterial secondary metabolites [32,40]. Nanoformulations of anticancer agents were also provided owing to simplifying delivery in a diversity of cancer states [155,160].
There are a lot of bioactive substances that have been isolated from different cyanobacteria species such as Lyngbya arboricola, Nostoc commune, Scytonema geitleri [46]. Rivularia [47], and Calothrix sp. [48] such as compounds 1 and nocuolin A (55), merocyclophane A (56) and B (57) also have anti-inflammatory and anticancer activities, but there is no detailed work on their nanoparticle applications in drug developments. This may be done in future research works with the application of biotechnological or synthetic approaches to the mass production of such compounds to be tested as nanoparticles in in vivo tests (Figure 10).

3.2. Cyanobacteria: Foes or Friend of Skins, Their Use in Cosmetics

Cyanobacteria produce toxic metabolites and are allergens that have negative effects on the health of human skin. Despite the fact that cytotoxicity and poisoning were seen with some cyanobacterial genera, this adverse effect was potentially described for anticancer applications, for instance some toxins that combat the progress of human adenocarcinomas [18]. Furthermore, recent studies showed that some compounds, like the carotenoids phytoene, phytofluene and astaxanthin, can play healing roles and have antiaging effects for skin’s health and appearance and are used in cosmetics [161]. Non Melanoma Skin Cancer (NMSCs) have increased since the past two decades. Sunscreen is recommended in these cases by healthcare specialists [162]. The exploitation of cyanobacteria’s applications in sunscreens and cosmetics is warranted owing to their abilities to protect skin and prevent UV radiation damage. New formulations of large scale production in the cosmetics industry contain mycosporine and mycosporinelike amino acids (MAAs) and their derivatives due to their maximum absorption in UV range [163,164,165]. Skin bleaching, as a parameter of beauty, has become common all over the world, mainly in Asia [166]. Tyrosine kinase inhibitors perform the best for this purpose. This enzyme catalyzes the rate-limiting step of pigmentation. We summarized the cyanobacterial bioactive compounds which are so far used in cosmetics and skin protection.
The synthetic chemicals in cosmetics can be very harmful and may be toxic to the skin and cause aging, in addition to their high costs. Consumer tastes also affect the cosmetics industry. Compared to traditional cosmetics, the natural cosmetics industry remains a smaller fraction of the market [167]. Compared to synthetic cosmetics, herbal beauty products are mild, biodegradable, safe and have few low side effects [168]. Beside cosmetics, there is another terminology called “cosmeceuticals”, which are cosmetic products with active ingredients that exert a pharmaceutical therapeutic benefit [39]. Cyanobacteria contain a wide variety of bioactive health defense molecules [40], including flavonoids, pigments (e.g., β-carotene, c-phycoerythrin, phycobiliproteins), phenols, saponins, steroids, tannins, terpenes and vitamins [39]. These active metabolites lead researchers to check their skin care function.
The testing of cosmetic products will continue to be carried out in compliance with the current adopted guidelines and keys to health and effectiveness testing that can be reproducibly and scientifically verified [169]. Herbal cosmetics can be used for a long time to improve skin’s appearance and enhance skin gloss [170]. There are several causes which decrease the brightness of the skin, such as damage to DNA [171] caused by free radicals [172] which damages the skin and increases the risk of aging [173]. The antioxidants of free radical scavenging and reactive oxygen species must also be tested [174]. Other causes may be ageing, including chronic inflammation [175], which reduces skin brightness and may also contribute to skin cancer [176]. Therefore, the molecules must be investigated as antiaging and tested for anti-inflammatory activity. The molecules should be tested as sunscreen protective devices for sun blocking, causing DNA damage, skin aging and tumorigenesis [177]. Desiccation is extremely hazardous to skin and thus hydrating agents are very useful for skin care and treatment [178].
In cosmetic applications, there are only a few reports of cyanobacteria; some molecules from different species of cyanobacteria show positive results in skin-care such as methanolic extracts of exopolysaccharides from Arthrospira platensis used as antioxidant [40]. SCY (1), an indol alkaloid pigment, synthesized by many strains of cyanobacteria, also used as a defender sunscreen [47,51], isolated from the terrestrial cyanobacterium communal of Nostoc and supported its free radical scavenging activities [50]. Numerous clinical and preclinical trials found that Spirulina possesses antioxidants, immunomodulators and anti-inflammatory activities which protect against oxidative stress by preventing and inhibiting lipid peroxidation, scavenging free radicals or by increasing superoxide dismutase (SOD) and catalase (CAT) activities [111]. The cell viability, wound healing activity and genotoxicity of S. platensis were examined, and the results were reported with 0.1% and 0.05% concentration showed a significant effect on L929 fibroblast cell line proliferation. Fibroblast are responsible for inflammation and scar formation during wound healing. Additionally, an incorporated skin cream with 1.125% S. platensis extract showed the highest proliferative effect on skin cells [179].
Mycotoxins, including trichothecenes and fumonisins, can also be involved in increasing oxidative stress. In addition, the main active compound phycocyanin is immunomodulatory and anti-inflammatory. It stimulates the production of antibodies and up- or downregulates the genes encoding cytokines [111]. As a result, all these drawbacks of using synthetic cosmetics have resulted in herbal cosmetics that have many benefits to preserving the health of the skin and enhancing its appearance [180]. Phenolic and flavonoid extracts from Oscillatoria sp., Chroococcidiopsis thermalis, Leptolyngbya sp., Calothrix sp. and Nostoc sp. have antioxidant activity [167]. Lycopene, which was found in Anabaena vaginicola and Nostoc calcicola, also showed antioxidant effects [181]. Polysaccharides from Nostac flagelliforme are used as free-radical scavengers [182]. A hot water extract of Nostochopsis sp. caused the inhibition of the tyrosinase enzyme [183] and displayed a major role in melanin synthesis [184] as it reduced α-melanocyte-stimulating hormone-induced melanin synthesis in B16 mouse melanoma cells and by acid and alkaline treatment [168]. Sacran, a novel sulfated polysaccharide, was extracted from Aphanothece sacrum and its anti-inflammatory activity was assessed [185]. Morone et al. [39] reported the bioactive potential of cyanobacteria that summarized the effects of aqueous and organic extracts from different species, MAAs, carotenoids, EPS, SKY and C-phycocyanin on anti-inflammatory, antioxidant, antiaging, moisture absorption and retention photoprotection and the whitening of the skin for cosmetics and cosmeceuticals, which were examined using different assays. Furthermore, the contents of the carotenoids and chlorophyll in the ethanolic extracts from the cyanobacteria species were determined by HPLC-PDA and employing the colorimetric tool of Folin–Ciocalteu to measure the total phenolic contents showed a dry biomass in mg GAE g−1, where the highest phenolic content of S. salina LEGE 06099 was reported as (2.45 mg GAE g−1) (p < 0.05), then Phormidium sp. LEGE 05292 exhibited (1.52 mg GAE g−1) and Cyanobium sp. LEGE 06113 displayed (1.41 mg GAE g−1) [38]. The carotenoid and chlorophyll utilized as antioxidant and free radical scavenging agents, could be used as well as skin antiaging and skin protection candidate against UV-induced photo-oxidation. Ultimately, with the increase in demand for natural products for body, skin, health and welfare treatments in spa and thalassotherapy centers, cyanobacteria may be seen as natural and ecofriendly sources from a significant bioactive constituent with advantageous effects for skin health, for the development of cosmetics industry investment. Therefore, there is a call for the promotion of research into cyanobacteria ingredients and their implications.

4. Total Synthesis and Stereochemical Determination of Marine Cyanobacteria Bioactive Compounds

Owing to their remarkable variety of structures and fascinating biological behavior, marine cyanobacteria have received exceptional interest from the scientific community [186]. While all of these are marine cyanobacteria advantages, the difficulty in the cultivation and processing of cyanobacteria and their resistance to laboratorial cultivation make it difficult to extract large quantities of natural products due adolescent constituents in species (i.e., 1 mg of 600 g cyanobacterium) [187]. Likewise, biological activities have not yet been investigated for the same purposes, including animal studies [188]. These issues can be addressed by successful large-scale processing by means of the synthesis of natural marine products, demonstrating a variety of ways to examine their biological activities [187]. Consequently, the overall synthesis of natural marine products has received much interest. Depsipeptides and polyketides are the most popular classes known for their synthesis and structure determination. Here, we are just highlighting one example from each group and their total synthetic route, as shown in Table 2. The most synthesized compounds and their structures were shown in Figure 11 and Figure 12.

4.1. Depsipeptides

Depsipeptides are natural polypeptides in which one or more of their amides is substituted with a hydroxy acid ester bond that is formed in the core ring structure. They come mainly from marine organisms, especially cyanobacteria [221]. It is interesting to note that various natural cyclic depsipeptides have both special structures and intriguing biological properties, such as antitumor, antifungal, antiviral, antibacterial, anthelmintic and antimicrobial properties. In particular, the strong effects of cyclic depsipeptides on tumor cells have resulted in a variety of clinical trials testing their chemotherapy potential [222]. Depsipeptides have been isolated from some of the most common marine animals, including Lyngbya majuscula, L. confervoides, L. bouillonii and Rivularia sp., as shown in Table 2. The cyclic lipodepsipeptide called 41 was isolated from the marine cyanobacterium L. majuscula was the subject of a complete synthesis of its isolated form by Gerwick and his coworkers. The EC50 = 20.1 ± 6.4 nM showed high ichthyotoxicity and neurotoxicity [187,205]. The full synthesis of jahanyne (63), a high-N-methylated lipopeptide containing acetylene, isolated from the marine cyanobacterium Lyngbya sp., induced a significant growth inhibition of both HL60 cells and HeLa, with IC50 values of 0.63 μM and 1.8 μM, respectively [198]. Scheme 1 displays the complete jahanyne synthesis. In general, the highly N-methylated acetylene containing lipopeptides has a wide range of antitumor, antibiotics and antifungal activities; thus, the chemical synthesis of this subfamily of lipopeptides is very important and can lead to new pharmaceutical discoveries [223]. The total synthesis of koshikalide (59) has also been completed, a 14-piece macrolide containing three olefines. The entire stereochemistry was developed to compare the different optical rotations of natural and synthesized koshikalides [224]. In 2010, compound 59 was isolated from a marine cyanobacterium Lyngbya sp., assembled in Koshika Prefecture, Shima City, Mie based on spectroscopic analyses, and its relative stereochemistry was created. It showed weak cytotoxicity with an IC50 value of 42 µg/mL against HeLa cells [190]. However, its complete stereochemistry could not be elucidated due to the scarcity of the sample (0.3 mg). So, the first total synthesis of koshikalides was performed to clarify the complete stereochemistry of koshikalides, as seen in Scheme 1.

4.2. Polyketides Peptide

The polyketide natural products are class of compounds that display a magnificent range of functional and structural diversity including antibiotic, anticancer, antifungal, antiparasitic and immunosuppressive properties [225]. So, scientists became concerned with these molecules and have done their best to assemble them [226]. Polyketides are separated from some of the most common species of cyanobacteria, such as Okeania sp., Symploca sp., Oscillatoria sp. and Paraliomixa miuraensis, which possess different biological activities, as shown in Table 2. For example, the total synthesis of janadolide (72), isolated from an Okeania sp. Compound 72 showed potent antitrypanosomal activity with an IC50 value of 47 nM, without cytotoxicity against human cells [210]. The steps of the total synthesis of 72 were due to the macrolactamization of the proline moiety and fatty acid moiety manifested by the amide bond, as seen in Scheme 2 [227]. Kurahyne B (74), a new kurahyne analog, has been separated from the marine cyanobacterium Okeania sp. collected in March 2013 at a depth of 0–1 m close to Jahana, Okinawa Prefecture, Japan. Its gross structure was elucidated using UV, IR, 1D and 2D NMR and HRESIMS spectroscopic analyses. The survival and proliferation of the cell lines (namely, the Hela and HL60 cells) was suppressed by compound 74, with IC50 values of 8.1 and 9.0 μM, respectively, whereas kurahyne B and kurahyne generate the same growth inhibition effect. The primary total synthesis of 73 was also accomplished [186]. Compound 73 is a novel acetylene-containing lipopeptide that was isolated from a marine cyanophyta Lyngbya sp. gathered in 2014. It has the same effect as 74, with IC50 values of 8.1 and 9.0 μM, respectively [228]. The absolute configuration was established by the total synthesis of 74 (3.6% overall yield in 14 steps). Additionally, the first total synthesis of 74 was also achieved (3.3% overall yield in 14 steps) [186].

5. Conclusions

Herein we are studying 91 compounds; 63 naturally occurring metabolites and 28 compounds synthesized from marine cyanobacteria. According to the best of our knowledge, the 28 synthesized compounds in this article have demonstrated important activities, including antibiotic, anticancer, antifungal, antiviral, anthelmintic, antimicrobial, antiparasitic, and immunosuppressive activities. These compounds have been isolated from the Lyngbya, Oscillatoria, Moorea, Okeania, Symploca, Rivularia, and Paraliomixa genera, and include molecules classified as depsipeptides and polyketides. However, the Lyngbya genus is associated with a polyphylla group which has had its taxonomic role revised. The potential for the discovery of new natural molecules and biosynthetic pathways associated with new cyanobacteria remains important and requires systematic exploration.
The naturally occurring metabolites were found in various species of 14 genera; Arthrospira, Lyngbya, Nostoc, Scytonema, Rivularia, Calothrix, Dapis, Okeania, Moorea, Cyanobium, Leptolyngbya, Symploca, Anabaena, Aphanothece, Oscillatoria, Paraliomixa. These metabolites can be categorized into eight chemical groups (including lipopeptides, polyketides, peptolide, depsipeptides, peptides, protein, polysaccharide and alkaloids) most of which are peptide by-products (over 70% of the families). No strong relationships were observed globally the between chemical groups and the specificity of the various types of bioactivity.
Clinically, we found prospective biomedical or behavioral research studies on 8 compounds/drugs and 4 as synthetic analogs—47, 48 and 59 derived from 45, and 46 derived from 44 isolated from marine cyanobacteria, which are designed to treat different diseases including treatments of different kinds from cancer, among them sarcoma, leukemia, lymphoma, liver, lung, kidney, prostate, and ovarian cancer.
Further in vivo studies remain necessary to precisely comprehend the mechanisms of action associated with cyanobacterial metabolites. For example, nostoflan exhibited potent antiviral activity against herpes simplex virus type 1 (HSV-1). Compound 40 displayed a similar effect on the human immunodeficiency virus type 1 with an IC90 of 1 mM employing cellular and cervical explant models. The inhibition of in vitro human viruses’ replication, including HCMV, HSV-1, HHV-6 and HIV-1, was impacted by the supplement of the broad-spectrum antiviral calcium spirulan. Taken together, these indicators resonate the potential notion regarding the role of the marine products in fighting of coronavirus [229], and thus warrant insight investigations to test the marine secondary against SARS-CoV-2 and particularly to face the COVID-19 pandemic.

Author Contributions

Writing—original draft preparation, S.A.M.K.; E.S.S.; and H.R.E.-S.; interpretation of the data and visualization, E.S.S.; E.M.S., A.R.J. and F.H.J.; revising and reviewing, M.E.R. and M.D.; writing—review and editing, M.M.A.-D.; G.-Y.K.; Z.G.; J.X.; M.A.M.A.-H. and H.R.E.-S.; idea and project administration, S.A.M.K. and H.R.E.-S. All authors have read and approved the manuscript.

Funding

We are very grateful to the Swedish Research links grant VR 2016-05885 and the Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Sweden, for the financial support.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Golubic, S.; Seong-Joo, L. Early cyanobacterial fossil record: Preservation, palaeoenvironments and identification. Eur. J. Phycol. 1999, 34, 339–348. [Google Scholar] [CrossRef]
  2. Singh, J.S.; Kumar, A.; Rai, A.N.; Singh, D.P. Cyanobacteria: A precious bio-resource in agriculture, ecosystem, and environmental sustainability. Front. Microbiol. 2016, 7, 529. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Fogg, G.E.; Stewart, W.D.P.; Fay, P.; Walsby, A.E. The Blue-Green Algae; Academic Press: New York, NY, USA, 1973; p. 459. [Google Scholar]
  4. Flombaum, P.; Gallegos, J.L.; Gordillo, R.A.; Rincón, J.; Zabala, L.L.; Jiao, N.; Karl, D.M.; Li, W.K.W.; Lomas, M.W.; Veneziano, D. Present and future global distributions of the marine cyanobacteria Prochlorococcus and Synechococcus. Proc. Natl. Acad. Sci. USA 2013, 110, 9824–9829. [Google Scholar] [CrossRef] [Green Version]
  5. Costa, M.; Garcia, M.; Costa-Rodrigues, J.; Costa, M.S.; Ribeiro, M.J.; Fernandes, M.H.; Barros, P.; Barreiro, A.; Vasconcelos, V.; Martins, R. Exploring bioactive properties of marine cyanobacteria isolated from the Portuguese coast: High potential as a source of anticancer compounds. Mar. Drugs 2014, 12, 98–114. [Google Scholar] [CrossRef] [Green Version]
  6. Bergman, B.; Sandh, G.; Lin, S.; Larsson, J.; Carpenter, E.J. Trichodesmium–a widespread marine cyanobacterium with unusual nitrogen fixation properties. FEMS Microbiol. Rev. 2013, 37, 286–302. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Rastogi, R.P.; Madamwar, D.; Incharoensakdi, A. Bloom dynamics of cyanobacteria and their toxins: Environmental health impacts and mitigation strategies. Front. Microbiol. 2015, 6, 1254. [Google Scholar] [CrossRef] [Green Version]
  8. Bocchi, S.; Malgioglio, A. Azolla-Anabaena as a biofertilizer for rice paddy fields in the Po Valley, a temperate rice area in Northern Italy. Int. J. Agron. 2010, 2010, 5. [Google Scholar] [CrossRef] [Green Version]
  9. Lincoln, E.P.; Wilkie, A.C.; French, B.T. Cyanobacterial process for renovating dairy wastewater. Biomass Bioenergy 1996, 10, 63–68. [Google Scholar] [CrossRef]
  10. Radakovits, R.; Jinkerson, R.E.; Darzins, A.; Posewitz, M.C. Genetic engineering of algae for enhanced biofuel production. Eukaryot. Cell 2010, 9, 486–501. [Google Scholar] [CrossRef] [Green Version]
  11. Garcia-Pichel, F.; Ramírez-Reinat, E.; Gao, Q. Microbial excavation of solid carbonates powered by P-type ATPase-mediated transcellular Ca2+ transport. Proc. Natl. Acad. Sci. USA 2010, 107, 21749–21754. [Google Scholar] [CrossRef] [Green Version]
  12. Whitton, B.A.; Potts, M. The Ecology of Cyanobacteria: Their Diversity in Time and Space; Springer Science & Business Media: New York, NY, USA; Boston, MA, USA; Dordrecht, The Netherlands; London, UK; Moscow, Russia, 2007. [Google Scholar]
  13. Najafi, A.; Moradinasab, M.; Nabipour, I. First record of microbiomes of sponges collected from the Persian Gulf, using tag pyrosequencing. Front. Microbiol. 2018, 9, 1500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Carpenter, E.J.; Foster, R.A. Marine cyanobacterial symbioses. In Cyanobacteria in Symbiosis; Springer: New York, NY, USA; Boston, MA, USA; Dordrecht, The Netherlands; London, UK; Moscow, Russia, 2002; pp. 11–17. [Google Scholar]
  15. Gozari, M.; Bahador, N.; Mortazavi, M.S.; Eftekhar, E.; Jassbi, A.R. An “olivomycin A” derivative from a sponge-associated Streptomyces sp. strain SP 85. 3 Biotech 2019, 9, 439. [Google Scholar] [CrossRef]
  16. Kaasalainen, U.; Fewer, D.P.; Jokela, J.; Wahlsten, M.; Sivonen, K.; Rikkinen, J. Cyanobacteria produce a high variety of hepatotoxic peptides in lichen symbiosis. Proc. Natl. Acad. Sci. USA 2012, 109, 5886–5891. [Google Scholar] [CrossRef] [Green Version]
  17. Anjum, K.; Abbas, S.Q.; Akhter, N.; Shagufta, B.I.; Shah, S.A.A.; Hassan, S.S.U. Emerging biopharmaceuticals from bioactive peptides derived from marine organisms. Chem. Biol. Drug. Des. 2017, 90, 12–30. [Google Scholar] [CrossRef]
  18. Zanchett, G.; Oliveira-Filho, E.C. Cyanobacteria and cyanotoxins: From impacts on aquatic ecosystems and human health to anticarcinogenic effects. Toxins 2013, 5, 1896–1917. [Google Scholar] [CrossRef]
  19. Gutiérrez, M.; Suyama, T.L.; Engene, N.; Wingerd, J.S.; Matainaho, T.; Gerwick, W.H. Apratoxin D, a potent cytotoxic cyclodepsipeptide from papua new guinea collections of the marine cyanobacteria Lyngbya majuscula and Lyngbya sordida. J. Nat. Prod. 2008, 71, 1099–1103. [Google Scholar] [CrossRef]
  20. Linington, R.G.; Edwards, D.J.; Shuman, C.F.; McPhail, K.L.; Matainaho, T.; Gerwick, W.H. Symplocamide A, a Potent Cytotoxin and Chymotrypsin Inhibitor from the Marine Cyanobacterium Symploca sp. J. Nat. Prod. 2008, 71, 22–27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Kurisawa, N.; Iwasaki, A.; Jeelani, G.; Nozaki, T.; Suenaga, K. Iheyamides A–C, Antitrypanosomal Linear Peptides Isolated from a Marine Dapis sp. Cyanobacterium. J. Nat. Prod. 2020, 83, 1684–1690. [Google Scholar] [CrossRef] [PubMed]
  22. Demay, J.; Bernard, C.; Reinhardt, A.; Marie, B. Natural products from cyanobacteria: Focus on beneficial activities. Mar. Drugs 2019, 17, 320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Jones, A.C.; Monroe, E.A.; Eisman, E.B.; Gerwick, L.; Sherman, D.H.; Gerwick, W.H. The unique mechanistic transformations involved in the biosynthesis of modular natural products from marine cyanobacteria. Nat. Prod. Rep. 2010, 27, 1048–1065. [Google Scholar] [CrossRef]
  24. Iwasaki, A.; Tadenuma, T.; Sumimoto, S.; Ohshiro, T.; Ozaki, K.; Kobayashi, K.; Teruya, T.; Tomoda, H.; Suenaga, K. Biseokeaniamides A, B, and C, sterol O-acyltransferase inhibitors from an Okeania sp. marine cyanobacterium. J. Nat. Prod. 2017, 80, 1161–1166. [Google Scholar] [CrossRef] [PubMed]
  25. Yu, H.-B.; Glukhov, E.; Li, Y.; Iwasaki, A.; Gerwick, L.; Dorrestein, P.C.; Jiao, B.-H.; Gerwick, W.H. Cytotoxic Microcolin Lipopeptides from the Marine Cyanobacterium Moorea producens. J. Nat. Prod. 2019, 82, 2608–2619. [Google Scholar] [CrossRef] [PubMed]
  26. Ozaki, K.; Iwasaki, A.; Sezawa, D.; Fujimura, H.; Nozaki, T.; Saito-Nakano, Y.; Suenaga, K.; Teruya, T. Isolation and Total Synthesis of Mabuniamide, a Lipopeptide from an Okeania sp. Marine Cyanobacterium. J. Nat. Prod. 2019, 82, 2907–2915. [Google Scholar] [CrossRef] [PubMed]
  27. Uzair, B.; Tabassum, S.; Rasheed, M.; Rehman, S.F. Exploring marine cyanobacteria for lead compounds of pharmaceutical importance. Sci. World J. 2012, 2012, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Agrawal, M.K. Antimicrobial Activity of Nostoc calcicola (Cyanobacteria) isolated from central India against human pathogens. Asian J. Pharm. 2016, 10. [Google Scholar] [CrossRef]
  29. Shah, S.; Akhter, N.; Auckloo, B.; Khan, I.; Lu, Y.; Wang, K.; Wu, B.; Guo, Y.-W.J.M.d. Structural diversity, biological properties and applications of natural products from cyanobacteria. A review. Mar. Drugs 2017, 15, 354. [Google Scholar] [CrossRef] [Green Version]
  30. Hossain, M.F.; Ratnayake, R.R.; Meerajini, K.; Wasantha Kumara, K.L. Antioxidant properties in some selected cyanobacteria isolated from fresh water bodies of Sri Lanka. Food Sci. Nutr. 2016, 4, 753–758. [Google Scholar] [CrossRef] [Green Version]
  31. Sijtsma, L.; De Swaaf, M.E. Biotechnological production and applications of the ω-3 polyunsaturated fatty acid docosahexaenoic acid. Appl. Microbiol. Biotechnol. 2004, 64, 146–153. [Google Scholar] [CrossRef]
  32. Singh, R.; Parihar, P.; Singh, M.; Bajguz, A.; Kumar, J.; Singh, S.; Singh, V.P.; Prasad, S.M. Uncovering potential applications of cyanobacteria and algal metabolites in biology, agriculture and medicine: Current status and future prospects. Front. Microbiol. 2017, 8. [Google Scholar] [CrossRef] [Green Version]
  33. Abed, R.; Dobretsov, S.; Sudesh, K. Application of cyanobacteria in biotechnology. J. Appl. Microbiol. 2008, 106, 1–12. [Google Scholar] [CrossRef]
  34. Ananyev, G.M.; Skizim, N.J.; Dismukes, G.C. Enhancing biological hydrogen production from cyanobacteria by removal of excreted products. J. Biotechnol. 2012, 162, 97–104. [Google Scholar] [CrossRef]
  35. Zahra, Z.; Choo, D.H.; Lee, H.; Parveen, A. Cyanobacteria: Review of current potentials and applications. Environments 2020, 7, 13. [Google Scholar] [CrossRef] [Green Version]
  36. Bajpai, V.; Shukla, S.; Kang, S.-M.; Hwang, S.; Song, X.; Huh, Y.; Han, Y.-K.J.M.d. Developments of cyanobacteria for nano-marine drugs: Relevance of nanoformulations in cancer therapies. Mar. Drugs 2018, 16, 179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; Rodriguez-Torres, M.d.p.; Acosta–Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.; Swamy, M.K.; Sharma, S.; et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Morone, J.; Lopes, G.; Preto, M.; Vasconcelos, V.; Martins, R. Exploitation of filamentous and picoplanktonic cyanobacteria for cosmetic applications: Potential to improve skin structure and preserve dermal matrix components. Mar. Drugs 2020, 18, 486. [Google Scholar] [CrossRef] [PubMed]
  39. Morone, J.; Alfeus, A.; Vasconcelos, V.; Martins, R. Revealing the potential of cyanobacteria in cosmetics and cosmeceuticals—A new bioactive approach. Algal Res. 2019, 41, 101541. [Google Scholar] [CrossRef]
  40. Mourelle, M.; Gómez, C.; Legido, J.J.C. The potential use of marine microalgae and cyanobacteria in cosmetics and thalassotherapy. Cosmetics 2017, 4, 46. [Google Scholar] [CrossRef] [Green Version]
  41. Burja, A.M.; Banaigs, B.; Abou-Mansour, E.; Burgess, J.G.; Wright, P.C. Marine cyanobacteria—A prolific source of natural products. Tetrahedron 2001, 57, 9347–9377. [Google Scholar] [CrossRef]
  42. Gunasekera, S.P.; Ross, C.; Paul, V.J.; Matthew, S.; Luesch, H. Dragonamides C and D, linear lipopeptides from the marine cyanobacterium brown Lyngbya polychroa. J. Nat. Prod. 2008, 71, 887–890. [Google Scholar] [CrossRef]
  43. Kwan, J.C.; Rocca, J.R.; Abboud, K.A.; Paul, V.J.; Luesch, H. Total structure determination of grassypeptolide, a new marine cyanobacterial cytotoxin. Org. Lett. 2008, 10, 789–792. [Google Scholar] [CrossRef]
  44. Rastogi, R.P.; Sinha, R.P. Biotechnological and industrial significance of cyanobacterial secondary metabolites. Biotechnol. Adv. 2009, 27, 521–539. [Google Scholar] [CrossRef] [PubMed]
  45. Kurutas, E.B. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: Current state. Nutr. J. 2015, 15, 71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Pathak, J.; Richa, R.; Sonker, A.S.; Kannaujiya, V.K.; Sinha, R.P. Isolation and partial purification of scytonemin and mycosporine-like amino acids from biological crusts. J. Chem. Pharm. Res. 2015, 7, 362–371. [Google Scholar]
  47. Rastogi, R.P.; Sinha, R.P.; Incharoensakdi, A. Partial characterization, UV-induction and photoprotective function of sunscreen pigment, scytonemin from Rivularia sp. HKAR-4. Chemosphere 2013, 93, 1874–1878. [Google Scholar] [CrossRef]
  48. Dillon, J.G.; Castenholz, R.W. The synthesis of the UV-screening pigment, scytonemin, and photosynthetic performance in isolates from closely related natural populations of cyanobacteria (Calothrix sp.). Environ. Microbiol. 2003, 5, 484–491. [Google Scholar] [CrossRef]
  49. Stevenson, C.S.; Capper, E.A.; Roshak, A.K.; Marquez, B.; Grace, K.; Gerwick, W.H.; Jacobs, R.S.; Marshall, L.A. Scytonemin—A marine natural product inhibitor of kinases key in hyperproliferative inflammatory diseases. Inflamm. Res. 2002, 51, 112–114. [Google Scholar] [CrossRef] [PubMed]
  50. Matsui, K.; Nazifi, E.; Hirai, Y.; Wada, N.; Matsugo, S.; Sakamoto, T. The cyanobacterial UV-absorbing pigment scytonemin displays radical-scavenging activity. J. Gen. Appl. Microbiol. 2012, 58, 137–144. [Google Scholar] [CrossRef] [Green Version]
  51. Rastogi, R.P.; Incharoensakdi, A. Characterization of UV-screening compounds, mycosporine-like amino acids, and scytonemin in the cyanobacterium Lyngbya sp. CU2555. FEMS Microbiol. Ecol. 2014, 87, 244–256. [Google Scholar] [CrossRef] [Green Version]
  52. Takamatsu, S.; Hodges, T.W.; Rajbhandari, I.; Gerwick, W.H.; Hamann, M.T.; Nagle, D.G. Marine natural products as novel antioxidant prototypes. J. Nat. Prod. 2003, 66, 605–608. [Google Scholar] [CrossRef] [Green Version]
  53. Suh, H.J.; Lee, H.W.; Jung, J. Mycosporine glycine protects biological systems against photodynamic damage by quenching singlet oxygen with a high efficiency. Photochem. Photobiol. 2003, 78, 109–113. [Google Scholar] [CrossRef]
  54. Tan, B.L.; Norhaizan, M.E.; Liew, W.-P.-P.; Sulaiman Rahman, H. Antioxidant and oxidative stress: A mutual interplay in age-related diseases. Front. Pharm. 2018, 9, 1162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Aydaş, S.B.; Ozturk, S.; Aslım, B. Phenylalanine ammonia lyase (PAL) enzyme activity and antioxidant properties of some cyanobacteria isolates. Food Chem. 2013, 136, 164–169. [Google Scholar] [CrossRef] [PubMed]
  56. Guerreiro, A.; Andrade, M.A.; Menezes, C.; Vilarinho, F.; Dias, E. Antioxidant and cytoprotective properties of cyanobacteria: Potential for biotechnological applications. Toxins 2020, 12, 548. [Google Scholar] [CrossRef] [PubMed]
  57. Minic, S.L.; Milcic, M.; Stanic-Vucinic, D.; Radibratovic, M.; Sotiroudis, T.G.; Nikolic, M.R.; Velickovic, T.Ć. Phycocyanobilin, a bioactive tetrapyrrolic compound of blue-green alga Spirulina, binds with high affinity and competes with bilirubin for binding on human serum albumin. RSC Adv. 2015, 5, 61787–61798. [Google Scholar] [CrossRef] [Green Version]
  58. Mishra, P.; Singh, V.P.; Prasad, S.M. Spirulina and its nutritional importance: A possible approach for development of functional food. Biochem. Pharmacol. 2014, 3, e171. [Google Scholar]
  59. Deo, S.K.; Pandey, R.; Jha, S.K.; Singh, J.; Sodhi, K.S. Spirulina: The single cell protein. Indo Am. J. Pharm. Res. 2014, 4, 221–2217. [Google Scholar]
  60. Miranda, M.S.; Cintra, R.G.; Barros, S.B.d.M.; Mancini-Filho, J. Antioxidant activity of the microalga Spirulina maxima. Braz. J. Med. Biol. Res. 1998, 31, 1075–1079. [Google Scholar] [CrossRef]
  61. Al-Dhabi, N.A.; Valan Arasu, M. Quantification of phytochemicals from commercial Spirulina products and their antioxidant activities. J. Evid. Based Complement. Altern. Med. 2016, 2016. [Google Scholar] [CrossRef] [Green Version]
  62. Yousefi, R.; Mottaghi, A.; Saidpour, A. Spirulina platensis effectively ameliorates anthropometric measurements and obesity-related metabolic disorders in obese or overweight healthy individuals: A randomized controlled trial. Complement. Ther. Med. 2018, 40, 106–112. [Google Scholar] [CrossRef] [PubMed]
  63. Sommella, E.; Conte, G.M.; Salviati, E.; Pepe, G.; Bertamino, A.; Ostacolo, C.; Sansone, F.; Prete, F.D.; Aquino, R.P.; Campiglia, P. Fast profiling of natural pigments in different Spirulina (Arthrospira platensis) dietary supplements by DI-FT-ICR and evaluation of their antioxidant potential by pre-column DPPH-UHPLC assay. Molecules 2018, 23, 1152. [Google Scholar] [CrossRef] [Green Version]
  64. Moore, R.E.; Corbett, T.H.; Patterson, G.M.L.; Valeriote, F.A. The search for new antitumor drugs from blue-green algae. Curr. Pharm. Des. 1996, 2, 317–330. [Google Scholar]
  65. Hemscheidt, T.; Puglisi, M.P.; Larsen, L.K.; Patterson, G.M.L.; Moore, R.E.; Rios, J.L.; Clardy, J. Structure and biosynthesis of borophycin, a new boeseken complex of boric acid from a marine strain of the blue-green alga Nostoc linckia. J. Org. Chem. 1994, 59, 3467–3471. [Google Scholar] [CrossRef]
  66. Torres, F.A.E.; Passalacqua, T.G.; Velásquez, A.M.A.; de Souza, R.A.; Colepicolo, P.; Graminha, M.A.S. New drugs with antiprotozoal activity from marine algae: A review. Rev. Bras. Farmacogn. 2014, 24, 265–276. [Google Scholar] [CrossRef] [Green Version]
  67. Gross, H.; McPhail, K.; Goeger, D.; Valeriote, F.; Gerwick, W. Two cytotoxic stereoisomers of malyngamide C, 8- epi-malyngamide C and 8- O-acetyl-8- epi-malyngamide C, from the marine cyanobacterium Lyngbya majuscula. Phytochemistry 2010, 71, 1729–1735. [Google Scholar] [CrossRef] [Green Version]
  68. Bernardo, P.H.; Chai, C.L.L.; Heath, G.A.; Mahon, P.J.; Smith, G.D.; Waring, P.; Wilkes, B.A. Synthesis, electrochemistry, and bioactivity of the cyanobacterial calothrixins and related quinones. J. Med. Chem. 2004, 47, 4958–4963. [Google Scholar] [CrossRef]
  69. Leao, P.N.; Costa, M.; Ramos, V.; Pereira, A.R.; Fernandes, V.C.; Domingues, V.F.; Gerwick, W.H.; Vasconcelos, V.M.; Martins, R. Antitumor activity of hierridin B, a cyanobacterial secondary metabolite found in both filamentous and unicellular marine strains. PLoS ONE 2013, 8, e69562. [Google Scholar] [CrossRef] [Green Version]
  70. Luesch, H.; Moore, R.E.; Paul, V.J.; Mooberry, S.L.; Corbett, T.H. Isolation of dolastatin 10 from the marine cyanobacterium Symploca species VP642 and total stereochemistry and biological evaluation of its analogue symplostatin 1. J. Nat. Prod. 2001, 64, 907–910. [Google Scholar] [CrossRef] [PubMed]
  71. McPhail, K.L.; Medina, R.A.; Gerwick, W.H.; Goeger, D.E.; Capeon, T.L. Isolation, Purification, and Structure Elucidation of the Antiproliferative Compound Coibamide A. U.S. Patent 20120028905-A1, 2 February 2012. [Google Scholar]
  72. Gerwick, W.H.; Tan, L.T.; Sitachitta, N. Nitrogen-containing metabolites from marine cyanobacteria. Alkaloids Chem. Biol. 2001, 57, 75–184. [Google Scholar] [PubMed]
  73. Williams, P.G.; Yoshida, W.Y.; Moore, R.E.; Paul, V.J. Tasipeptins A and B: New cytotoxic depsipeptides from the marine cyanobacterium Symploca sp. J. Nat. Prod. 2003, 66, 620–624. [Google Scholar] [CrossRef] [PubMed]
  74. Simmons, T.L.; Nogle, L.M.; Media, J.; Valeriote, F.A.; Mooberry, S.L.; Gerwick, W.H. Desmethoxymajusculamide C, a cyanobacterial depsipeptide with potent cytotoxicity in both cyclic and ring-opened forms. J. Nat. Prod. 2009, 72, 1011–1016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. McPhail, K.L.; Correa, J.; Linington, R.G.; González, J.; Ortega-Barría, E.; Capson, T.L.; Gerwick, W.H. Antimalarial linear lipopeptides from a Panamanian strain of the marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2007, 70, 984–988. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Balunas, M.J.; Linington, R.G.; Tidgewell, K.; Fenner, A.M.; Urena, L.-D.; Togna, G.D.; Kyle, D.E.; Gerwick, W.H. Dragonamide E, a modified linear lipopeptide from Lyngbya majuscula with antileishmanial activity. J. Nat. Prod. 2010, 73, 60–66. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Sanchez, L.M.; Lopez, D.; Vesely, B.A.; Della Togna, G.; Gerwick, W.H.; Kyle, D.E.; Linington, R.G. Almiramides A− C: Discovery and development of a new class of leishmaniasis lead compounds. J. Med. Chem. 2010, 53, 4187–4197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Rickards, R.W.; Rothschild, J.M.; Willis, A.C.; de Chazal, N.M.; Kirk, J.; Kirk, K.; Saliba, K.J.; Smith, G.D. Calothrixins A and B, novel pentacyclic metabolites from Calothrix cyanobacteria with potent activity against malaria parasites and human cancer cells. Tetrahedron 1999, 55, 13513–13520. [Google Scholar] [CrossRef]
  79. Lee, J.-B.; Hayashi, T.; Hayashi, K.; Sankawa, U.; Maeda, M.; Nemoto, T.; Nakanishi, H. Further purification and structural analysis of calcium spirulan from Spirulina platensis. J. Nat. Prod. 1998, 61, 1101–1104. [Google Scholar] [CrossRef] [PubMed]
  80. Hayashi, T.; Hayashi, K.; Maeda, M.; Kojima, I. Calcium spirulan, an inhibitor of enveloped virus replication, from a blue-green alga Spirulina platensis. J. Nat. Prod. 1996, 59, 83–87. [Google Scholar] [CrossRef]
  81. Hayashi, K.; Hayashi, T.; Kojima, I. A Natural sulfated polysaccharide, calcium spirulan, isolated from Spirulina platensis: In vitro and ex vivo evaluation of anti-herpes simplex virus and anti-human immunodeficiency virus activities. AIDS Res. Hum. Retrovir. 1996, 12, 1463–1471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Rechter, S.; König, T.; Auerochs, S.; Thulke, S.; Walter, H.; Dörnenburg, H.; Walter, C.; Marschall, M. Antiviral activity of Arthrospira-derived spirulan-like substances. Antivir. Res. 2006, 72, 197–206. [Google Scholar] [CrossRef]
  83. Kanekiyo, K.; Lee, J.-B.; Hayashi, K.; Takenaka, H.; Hayakawa, Y.; Endo, S.; Hayashi, T. Isolation of an antiviral polysaccharide, nostoflan, from a terrestrial cyanobacterium, Nostoc flagelliforme. J. Nat. Prod. 2005, 68, 1037–1041. [Google Scholar] [CrossRef]
  84. Lokhande, K.B.; Apte, G.R.; Shrivastava, A.; Singh, A.; Pal, J.K.; Swamy, K.V.; Gupta, R.K. Sensing the interactions between carbohydrate-binding agents and N-linked glycans of SARS-CoV-2 spike glycoprotein using molecular docking and simulation studies. J. Biomol. Struct. Dyn. 2020, 1–19. [Google Scholar] [CrossRef]
  85. Pendyala, B.; Patras, A.; Dash, C. Phycobilins as potent food bioactive broad-spectrum inhibitor compounds against Mpro and PLpro of SARS-CoV-2 and other coronaviruses: A preliminary Study. bioRxiv 2020. [Google Scholar] [CrossRef]
  86. Naidoo, D.; Roy, A.; Kar, P.; Mutanda, T.; Anandraj, A. Cyanobacterial metabolites as promising drug leads against the Mpro and PLpro of SARS-CoV-2: An in silico analysis. J. Biomol. Struct. Dyn. 2020, 1–13. [Google Scholar] [CrossRef]
  87. Schwarzer, D.; Finking, R.; Marahiel, M.A. Nonribosomal peptides: From genes to products. Nat. Prod. Rep. 2003, 20, 275–287. [Google Scholar] [CrossRef] [PubMed]
  88. Lichota, A.; Gwozdzinski, K. Anticancer Activity of Natural Compounds from Plant and Marine Environment. Int. J. Mol. Sci. 2018, 19, 3533. [Google Scholar] [CrossRef] [Green Version]
  89. Gheda, S.F.; Ismail, G.A. Natural products from some soil cyanobacterial extracts with potent antimicrobial, antioxidant and cytotoxic activities. Anais Acad. Bras. Ciênc. 2019, 92, e20190934. [Google Scholar] [CrossRef] [PubMed]
  90. Jordan, M.A.; Wilson, L. Microtubules and actin filaments: Dynamic targets for cancer chemotherapy. Curr. Opin. Cell Biol. 1998, 10, 123–130. [Google Scholar] [CrossRef]
  91. Dixit, R.B.; Suseela, M.R. Cyanobacteria: Potential candidates for drug discovery. Antonie Leeuwenhoek 2013, 103, 947–961. [Google Scholar] [CrossRef]
  92. Tan, L.T. Bioactive natural products from marine cyanobacteria for drug discovery. Phytochemistry 2007, 68, 954–979. [Google Scholar] [CrossRef]
  93. Drugbank. Available online: https://www.drugbank.ca/drugs/DB12730 (accessed on 20 December 2020).
  94. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00005579 (accessed on 20 December 2020).
  95. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00003626 (accessed on 20 December 2020).
  96. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00003914 (accessed on 20 December 2020).
  97. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00003557 (accessed on 20 December 2020).
  98. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00003778 (accessed on 20 December 2020).
  99. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00003693 (accessed on 20 December 2020).
  100. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00003677 (accessed on 20 December 2020).
  101. Liu, L.; Rein, K.S. New peptides isolated from Lyngbya species: A review. Mar. Drugs 2010, 8, 1817–1837. [Google Scholar] [CrossRef] [Green Version]
  102. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00068211 (accessed on 20 December 2020).
  103. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00082134 (accessed on 20 December 2020).
  104. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00078455 (accessed on 21 December 2020).
  105. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00431223 (accessed on 21 December 2020).
  106. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00546052 (accessed on 21 December 2020).
  107. Drugbank. Available online: http://www.drugbank.ca/drugs/DB13916 (accessed on 21 December 2020).
  108. Patterson, G.M.L.; Bolis, C.M. Fungal cellwall polysaccharides elicit an antifungal secondary metabolite (phytoalexin) in the cyanobacterium scytonema ocelutum 2. J. Phycol. 1997, 33, 54–60. [Google Scholar] [CrossRef]
  109. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT01677611 (accessed on 21 December 2020).
  110. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT00064220 (accessed on 21 December 2020).
  111. Wu, Q.; Liu, L.; Miron, A.; Klímová, B.; Wan, D.; Kuča, K. The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: An overview. Arch. Toxicol. 2016, 90, 1817–1840. [Google Scholar] [CrossRef]
  112. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT02886676 (accessed on 21 December 2020).
  113. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT02817620 (accessed on 21 December 2020).
  114. Aráoz, R.; Molgó, J.; de Marsac, N.T. Neurotoxic cyanobacterial toxins. Toxicon 2010, 56, 813–828. [Google Scholar] [CrossRef] [PubMed]
  115. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT02916966 (accessed on 21 December 2020).
  116. Raja, R.; Hemaiswarya, S.; Ganesan, V.; Carvalho, I.S. Recent developments in therapeutic applications of Cyanobacteria. Crit. Rev. Microbiol. 2016, 42, 394–405. [Google Scholar] [CrossRef]
  117. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT02928042 (accessed on 21 December 2020).
  118. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT03219931 (accessed on 21 December 2020).
  119. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT02241161 (accessed on 21 December 2020).
  120. Clinicaltrials. Available online: https://www.clinicaltrials.gov/NCT03004196 (accessed on 21 December 2020).
  121. Lotfi, H.; Sheervalilou, R.; Zarghami, N. An update of the recombinant protein expression systems of Cyanovirin-N and challenges of preclinical development. BioImpacts 2018, 8, 139. [Google Scholar] [CrossRef] [Green Version]
  122. Beltran, E.C.; Neilan, B.A.J.A.; Microbiology, E. Geographical segregation of the neurotoxin-producing cyanobacterium Anabaena circinalis. Appl. Environ. Microbiol. 2000, 66, 4468–4474. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Sierosławska, A.; Rymuszka, A.; Kalinowska, R.; Skowroński, T.; Bownik, A.; Pawlik-Skowrońska, B. Toxicity of cyanobacterial bloom in the eutrophic dam reservoir (Southeast Poland). Environ. Toxicol. Chem. Int. J. 2010, 29, 556–560. [Google Scholar] [CrossRef]
  124. Boyd, M.R.; Gustafson, K.R.; McMahon, J.B.; Shoemaker, R.H.; O’Keefe, B.R.; Mori, T.; Gulakowski, R.J.; Wu, L.; Rivera, M.I.; Laurencot, C.M.; et al. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: Potential applications to microbicide development. Antivir. Res. 1997, 41, 1521–1530. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Gustafson, K.R.; Sowder, R.C., II; Henderson, L.E.; Cardellina, J.H., II; McMahon, J.B.; Rajamani, U.; Pannell, L.K.; Boyd, M.R. Isolation, primary sequence determination, and disulfide bond structure of cyanovirin-n, an anti-hiv (human immunodeficiency virus) protein from the cyanobacterium nostoc ellipsosporum. Biochem. Biophys. Res. Commun. 1997, 238, 223–228. [Google Scholar] [CrossRef]
  126. Buffa, V.; Stieh, D.; Mamhood, N.; Hu, Q.; Fletcher, P.; Shattock, R.J. Cyanovirin-N potently inhibits human immunodeficiency virus type 1infection in cellular and cervical explant models. J. Gen. Virol. 2009, 90, 234–243. [Google Scholar] [CrossRef] [Green Version]
  127. Stewart, J.B.; Bornemann, V.; JIAN, L.; Moore, R.E.; Caplan, F.R.; Karuso, H.; Larsen, L.K.; Patterson, G.M. Cytotoxic, fungicidal nucleosides from blue green algae belonging to the Scytonemataceae. J. Antibiot. 1988, 41, 1048–1056. [Google Scholar] [CrossRef] [Green Version]
  128. Bastea, L.I.; Hollant, L.M.; Döppler, H.R.; Reid, E.M.; Storz, P. Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death. Sci. Rep. 2019, 9, 1–10. [Google Scholar] [CrossRef] [Green Version]
  129. Stockwin, L.H.; Sherry, X.Y.; Stotler, H.; Hollingshead, M.G.; Newton, D.L. ARC (NSC 188491) has identical activity to Sangivamycin (NSC 65346) including inhibition of both P-TEFb and PKC. BMC Cancer 2009, 9, 63. [Google Scholar] [CrossRef] [Green Version]
  130. Wang, H.; Fewer, D.P.; Sivonen, K. Genome mining demonstrates the widespread occurrence of gene clusters encoding bacteriocins in cyanobacteria. PLoS ONE 2011, 6, e22384. [Google Scholar] [CrossRef] [Green Version]
  131. Desriac, F.; Defer, D.; Bourgougnon, N.; Brillet, B.; Le Chevalier, P.; Fleury, Y. Bacteriocin as weapons in the marine animal-associated bacteria warfare: Inventory and potential applications as an aquaculture probiotic. Mar. Drugs 2010, 8, 1153–1177. [Google Scholar] [CrossRef] [Green Version]
  132. Cotter, P.D.; Ross, R.P.; Hill, C. Bacteriocins—A viable alternative to antibiotics? Nat. Rev. Microbiol. 2013, 11, 95–105. [Google Scholar] [CrossRef]
  133. Ishii, K.; Katoh, T.; Okuwaki, Y.; Hayashi, O. Influence of dietary Spirulina platensis on IgA level in human saliva. J. Kagawa Nutr. Univ. 1999, 30, 27–33. [Google Scholar]
  134. Tantong, S.; Incharoensakdi, A.; Sirikantaramas, S.; Lindblad, P. Purification, potential of synechocystis PCC 6803 as a novel cyanobacterial chassis for heterologous expression of enzymes in the trans-resveratrol biosynthetic pathway. Protein Expr. Purif. 2016, 121, 163–168. [Google Scholar] [CrossRef] [PubMed]
  135. Vallianou, N.G.; Evangelopoulos, A.; Kazazis, C. Resveratrol and diabetes. Rev. Diabetic Stud. 2013, 10, 236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Ott, P.A.; Pavlick, A.C.; Johnson, D.B.; Hart, L.L.; Infante, J.R.; Luke, J.J.; Lutzky, J.; Rothschild, N.; Spitler, L.; Cowey, C.L. A phase 2 study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma. European Society for Medical Oncology. Ann. Oncol. 2016, 27, vi393. [Google Scholar] [CrossRef] [Green Version]
  137. Deng, C.; Pan, B.; O’Connor, O.A. Brentuximab vedotin. Clin. Cancer Res. 2013, 19, 22–27. [Google Scholar] [CrossRef] [Green Version]
  138. Kulasooriya, S.A. Cyanobacteria: Pioneers of planet earth. Ceylon J. Sci. (Bio. Sci.) 2011, 40, 71–88. [Google Scholar] [CrossRef] [Green Version]
  139. Kulasooriya, S.A.; Magana-Arachchi, D.N. Nitrogen fixing cyanobacteria: Their diversity, ecology and utilisation with special reference to rice cultivation. J. Nat. Sci. Foundat. Sri Lanka 2016, 44, 111–128. [Google Scholar] [CrossRef] [Green Version]
  140. Vijayakumar, S.; Menakha, M. Pharmaceutical applications of cyanobacteria—A review. J. Acute Med. 2015, 5, 15–23. [Google Scholar] [CrossRef] [Green Version]
  141. Kumar, J.; Singh, D.; Tyagi, M.B.; Kumar, A. Cyanobacteria: Applications in biotechnology. In Cyanobacteria; Elsevier: Amsterdam, The Netherlands, 2019; pp. 327–346. [Google Scholar]
  142. Angermayr, S.A.; Hellingwerf, K.J.; Lindblad, P.; de Mattos, M.J.T. Energy biotechnology with cyanobacteria. Curr. Opin. Biotechnol. 2009, 20, 257–263. [Google Scholar] [CrossRef] [PubMed]
  143. Pulz, O.; Gross, W. Valuable products from biotechnology of microalgae. Appl. Microbiol. Biotechnol. 2004, 65, 635–648. [Google Scholar] [CrossRef]
  144. De Farias Silva, C.E.; Bertucco, A. Bioethanol from microalgae and cyanobacteria: A review and technological outlook. Process Biochem. 2016, 51, 1833–1842. [Google Scholar] [CrossRef]
  145. Deviram, G.; Mathimani, T.; Anto, S.; Ahamed, T.S.; Ananth, D.A.; Pugazhendhi, A. Applications of microalgal and cyanobacterial biomass on a way to safe, cleaner and a sustainable environment. J. Clean. Prod. 2020, 253, 119770. [Google Scholar] [CrossRef]
  146. Mirsasaani, S.S.; Hemati, M.; Dehkord, E.S.; Yazdi, G.T.; Poshtiri, D.A. Nanotechnology and nanobiomaterials in dentistry. In Nanobiomaterials in Clinical Dentistry; Elsevier: Amsterdam, The Netherlands, 2019; pp. 19–37. [Google Scholar]
  147. Nair, H.B.; Sung, B.; Yadav, V.R.; Kannappan, R.; Chaturvedi, M.M.; Aggarwal, B.B. Delivery of antiinflammatory nutraceuticals by nanoparticles for the prevention and treatment of cancer. Biochem. Pharmacol. 2010, 80, 1833–1843. [Google Scholar] [CrossRef] [Green Version]
  148. Mohanpuria, P.; Rana, N.K.; Yadav, S.K. Biosynthesis of nanoparticles: Technological concepts and future applications. J. Nanopart. Res. 2008, 10, 507–517. [Google Scholar] [CrossRef]
  149. Elghazawy, N.H.; Hefnawy, A.; Sedky, N.K.; El-Sherbiny, I.M.; Arafa, R.K. Preparation and nanoformulation of new quinolone scaffold-based anticancer agents: Enhancing solubility for better cellular delivery. Eur. J. Pharm. Sci. 2017, 105, 203–211. [Google Scholar] [CrossRef]
  150. Kubik, T.; Bogunia-Kubik, K.; Sugisaka, M. Nanotechnology on duty in medical applications. Curr. Pharm. Biotechnol. 2005, 6, 17–33. [Google Scholar] [CrossRef] [PubMed]
  151. Vijayan, S.R.; Santhiyagu, P.; Ramasamy, R.; Arivalagan, P.; Kumar, G.; Ethiraj, K.; Ramaswamy, B.R. Seaweeds: A resource for marine bionanotechnology. Enzyme Microb. Technol. 2016, 95, 45–57. [Google Scholar] [CrossRef] [PubMed]
  152. Manivasagan, P.; Bharathiraja, S.; Moorthy, M.S.; Oh, Y.-O.; Seo, H.; Oh, J. Marine biopolymer-based nanomaterials as a novel platform for theranostic applications. Polym. Rev. 2017, 57, 631–667. [Google Scholar] [CrossRef]
  153. Cardoso, M.J.; Costa, R.R.; Mano, J.F. Marine origin polysaccharides in drug delivery systems. Mar. Drugs 2016, 14, 34. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Lengke, M.F.; Fleet, M.E.; Southam, G. Biosynthesis of silver nanoparticles by filamentous cyanobacteria from a silver (I) nitrate complex. Langmuir 2007, 23, 2694–2699. [Google Scholar] [CrossRef] [PubMed]
  155. Patel, V.; Berthold, D.; Puranik, P.; Gantar, M. Screening of cyanobacteria and microalgae for their ability to synthesize silver nanoparticles with antibacterial activity. Biotechnol. Rep. 2015, 5, 112–119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. MubarakAli, D.; Sasikala, M.; Gunasekaran, M.; Thajuddin, N. Biosynthesis and characterization of silver nanoparticles using marine cyanobacterium, Oscillatoria willei NTDM01. Dig. J. Nanomater. Biostruct. 2011, 6, 385–390. [Google Scholar]
  157. Brayner, R.; Barberousse, H.; Hemadi, M.; Djedjat, C.; Yéprémian, C.; Coradin, T.; Livage, J.; Fiévet, F.; Couté, A. Cyanobacteria as bioreactors for the synthesis of Au, Ag, Pd, and Pt nanoparticles via an enzyme-mediated route. J. Nanosci. Nanotechnol. 2007, 7, 2696–2708. [Google Scholar] [CrossRef]
  158. Shanmugam, R.; Chelladurai, M.; Paulmar, K.; Vanaja, M.; Gnanajobitha, G.; Gurusamy, A. Intracellular and extracellular biosynthesis of silver nanoparticles by using marine bacteria Vibrio alginolyticus. Nanosci. Nanotechnol. 2013, 3, 21–25. [Google Scholar]
  159. Delneuville, C.; Danloy, E.P.; Wang, L.; Su, B.-L. Single cyanobacteria@ silica porous microcapsules via a sol–gel layer by layer for heavy-metal remediation. J. Sol. Gel. Sci. Technol. 2019, 89, 244–254. [Google Scholar] [CrossRef]
  160. Zhang, Y.S.; Zhang, Y.-N.; Zhang, W. Cancer-on-a-chip systems at the frontier of nanomedicine. Drug Dis. Today 2017, 22, 1392–1399. [Google Scholar] [CrossRef] [PubMed]
  161. Meléndez-Martínez, A.J.; Stinco, C.M.; Mapelli-Brahm, P. Skin carotenoids in public health and nutricosmetics: The emerging roles and applications of the UV radiation-absorbing colourless carotenoids phytoene and phytofluene. Nutrients 2019, 11, 1093. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Halpern, A.C.; Kopp, L.J. Awareness, knowledge and attitudes to non-melanoma skin cancer and actinic keratosis among the general public. Int. J. Dermatol. 2005, 44, 107–111. [Google Scholar] [CrossRef]
  163. Conde, F.R.; Churio, M.S.; Previtali, C.M. The photoprotector mechanism of mycosporine-like amino acids. Excited-state properties and photostability of porphyra-334 in aqueous solution. J. Photochem. Photobiol. B Biol. 2000, 56, 139–144. [Google Scholar] [CrossRef]
  164. Dunlap, W.C.; Chalker, B.E.; Bandaranayake, W.M.; Wu Won, J.J. Nature’s sunscreen from the Great Barrier Reef, Australia. Int. J. Cosmet. Sci. 1998, 20, 41–51. [Google Scholar] [CrossRef]
  165. Bhatia, S.; Garg, A.; Sharma, K.; Kumar, S.; Sharma, A.; Purohit, A.P. Mycosporine and mycosporine-like amino acids: A paramount tool against ultra violet irradiation. Pharmacogn. Rev. 2011, 5, 138. [Google Scholar] [CrossRef] [Green Version]
  166. Li, E.P.H.; Min, H.J.; Belk, R.W. Skin lightening and beauty in four Asian cultures. ACR N. Am. Adv. 2008, 35, 444–449. [Google Scholar]
  167. Joshi, L.S.; Pawar, H.A. Herbal cosmetics and cosmeceuticals: An overview. Nat. Prod. Chem. Res. 2015, 3, 170. [Google Scholar] [CrossRef]
  168. Chanchal, D.; Swarnlata, S. Novel approaches in herbal cosmetics. J. Cosmet. Dermatol. 2008, 7, 89–95. [Google Scholar] [CrossRef]
  169. Dreno, B.; Araviiskaia, E.; Berardesca, E.; Bieber, T.; Hawk, J.; Sanchez-Viera, M.; Wolkenstein, P. The science of dermocosmetics and its role in dermatology. J. Eur. Acad. Dermatol. Venereol. 2014, 28, 1409–1417. [Google Scholar] [CrossRef]
  170. Datta, H.S.; Paramesh, R. Trends in aging and skin care: Ayurvedic concepts. J. Ayurveda Integr. Med. 2010, 1, 110. [Google Scholar] [CrossRef] [Green Version]
  171. Ou, H.-L.; Schumacher, B. DNA damage responses and p53 in the aging process. Blood 2018, 131, 488–495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  172. Dizdaroglu, M.; Jaruga, P. Mechanisms of free radical-induced damage to DNA. Free Radic. Res. 2012, 46, 382–419. [Google Scholar] [CrossRef] [PubMed]
  173. Liochev, S.I. Reactive oxygen species and the free radical theory of aging. Free Radic. Biol. Med. 2013, 60, 1–4. [Google Scholar] [CrossRef] [PubMed]
  174. Shahzad, M.; Shabbir, A.; Wojcikowski, K.; Wohlmuth, H.; Gobe, G.C. The antioxidant effects of Radix Astragali (Astragalus membranaceus and related species) in protecting tissues from injury and disease. Curr. Drug Targets 2016, 17, 1331–1340. [Google Scholar] [CrossRef]
  175. Fougère, B.; Boulanger, E.; Nourhashémi, F.; Guyonnet, S.; Cesari, M. RETRACTED: Chronic Inflammation: Accelerator of Biological Aging. J. Gerontol. A 2017, 72, 1218–1225. [Google Scholar] [CrossRef] [Green Version]
  176. Maru, G.B.; Gandhi, K.; Ramchandani, A.; Kumar, G. The role of inflammation in skin cancer. In Inflammation and Cancer; Springer: New York, NY, USA; Boston, MA, USA; Dordrecht, The Netherlands; London, UK; Moscow, Russia, 2014; pp. 437–469. [Google Scholar]
  177. Radice, M.; Manfredini, S.; Ziosi, P.; Dissette, V.; Buso, P.; Fallacara, A.; Vertuani, S. Herbal extracts, lichens and biomolecules as natural photo-protection alternatives to synthetic UV filters. A systematic review. Fitoterapia 2016, 114, 144–162. [Google Scholar] [CrossRef]
  178. Derikvand, P.; Llewellyn, C.A.; Purton, S. Cyanobacterial metabolites as a source of sunscreens and moisturizers: A comparison with current synthetic compounds. Eur. J. Phycol. 2017, 52, 43–56. [Google Scholar] [CrossRef]
  179. Gunes, S.; Tamburaci, S.; Dalay, M.C.; Deliloglu Gurhan, I. in vitro evaluation of Spirulina platensis extract incorporated skin cream with its wound healing and antioxidant activities. Pharm. Biol. 2017, 55, 1824–1832. [Google Scholar] [CrossRef] [Green Version]
  180. Saha, R. Cosmeceuticals and herbal drugs: Practical uses. Int. J. Pharm. Sci. Res. 2012, 3, 59–65. [Google Scholar]
  181. Hashtroudi, M.S.; Shariatmadari, Z.; Riahi, H.; Ghassempour, A. Analysis of Anabaena vaginicola and Nostoc calcicola from Northern Iran, as rich sources of major carotenoids. Food Chem. 2013, 136, 1148–1153. [Google Scholar] [CrossRef]
  182. Hamed, I. The evolution and versatility of microalgal biotechnology: A review. Compr. Rev. Food Sci. F 2016, 15, 1104–1123. [Google Scholar] [CrossRef]
  183. Yabuta, Y.; Hashimoto, E.; Takeuchi, T.; Sakaki, S.; Yamaguchi, Y.; Takenaka, H.; Watanabe, F. Characterization of a hot water extract of an edible cyanobacterium Nostochopsis sp. for use as an ingredient in cosmetics. Food Sci. Technol. Res. 2014, 20, 505–507. [Google Scholar] [CrossRef] [Green Version]
  184. Pillaiyar, T.; Manickam, M.; Namasivayam, V. Skin whitening agents: Medicinal chemistry perspective of tyrosinase inhibitors. J. Enzyme Inhibit. Med. Chem. 2017, 32, 403–425. [Google Scholar] [CrossRef] [Green Version]
  185. Ngatu, N.R.; Okajima, M.K.; Yokogawa, M.; Hirota, R.; Eitoku, M.; Muzembo, B.A.; Dumavibhat, N.; Takaishi, M.; Sano, S.; Kaneko, T. Anti-inflammatory effects of sacran, a novel polysaccharide from Aphanothece sacrum, on 2, 4, 6-trinitrochlorobenzene–induced allergic dermatitis in vivo. Ann. Allergy Asthma Immunol. 2012, 108, 117–122. [Google Scholar] [CrossRef]
  186. Okamoto, S.; Iwasaki, A.; Ohno, O.; Suenaga, K. Isolation and structure of kurahyne B and total synthesis of the kurahynes. J. Nat. Prod. 2015, 78, 2719–2725. [Google Scholar] [CrossRef]
  187. Hamada, Y.; Shioiri, T. Recent progress of the synthetic studies of biologically active marine cyclic peptides and depsipeptides. Chem. Rev. 2005, 105, 4441–4482. [Google Scholar] [CrossRef]
  188. Shinomiya, S.; Iwasaki, A.; Ohno, O.; Suenaga, K.J.P. Total synthesis and stereochemical determination of yoshinone A. Phytochemistry 2016, 132, 109–114. [Google Scholar] [CrossRef]
  189. Ogawa, H.; Iwasaki, A.; Sumimoto, S.; Iwatsuki, M.; Ishiyama, A.; Hokari, R.; Otoguro, K.; Ōmura, S.; Suenaga, K. Isolation and total synthesis of hoshinolactam, an antitrypanosomal lactam from a marine cyanobacterium. Org. Lett. 2017, 19, 890–893. [Google Scholar] [CrossRef]
  190. Iwasaki, A.; Teruya, T.; Suenaga, K. Isolation and structure of koshikalide, a 14-membered macrolide from the marine cyanobacterium Lyngbya sp. Tetrahedron Lett. 2010, 51, 959–960. [Google Scholar] [CrossRef]
  191. Chen, J.; Forsyth, C.J. Total synthesis of the marine cyanobacterial cyclodepsipeptide apratoxin A. Proc. Natl. Acad. Sci. USA 2004, 101, 12067–12072. [Google Scholar] [CrossRef] [Green Version]
  192. Luesch, H.; Yoshida, W.Y.; Moore, R.E.; Paul, V.J.; Corbett, T.H. Total structure determination of Apratoxin A, a potent novel cytotoxin from the marine Cyanobacterium Lyngbya majuscula. J. Am. Chem. Soc. 2001, 123, 5418–5423. [Google Scholar] [CrossRef]
  193. Luo, D.; Chen, Q.-Y.; Luesch, H. Total synthesis of the potent marine-derived elastase inhibitor lyngbyastatin 7 and in vitro biological evaluation in model systems for pulmonary diseases. J. Org. Chem. 2015, 81, 532–544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Taori, K.; Matthew, S.; Rocca, J.R.; Paul, V.J.; Luesch, H.J. Lyngbyastatins 5–7, potent elastase inhibitors from Floridian marine cyanobacteria, Lyngbya spp. J. Nat. Prod. 2007, 70, 1593–1600. [Google Scholar] [CrossRef] [PubMed]
  195. Fuwa, H.; Okuaki, Y.; Yamagata, N.; Sasaki, M. Total synthesis, stereochemical reassignment, and biological evaluation of (−)-Lyngbyaloside B. Angew. Chem. 2015, 127, 882–887. [Google Scholar] [CrossRef]
  196. Luesch, H.; Yoshida, W.Y.; Harrigan, G.G.; Doom, J.P.; Moore, R.E.; Paul, V.J. Lyngbyaloside B, a new glycoside macrolide from a Palauan marine cyanobacterium, Lyngbya sp. J. Nat. Prod. 2002, 65, 1945–1948. [Google Scholar] [CrossRef] [PubMed]
  197. Takayanagi, A.; Iwasaki, A.; Suenaga, K. Total synthesis and stereochemical reassignment of maedamide. Tetrahedron Lett. 2015, 56, 4947–4949. [Google Scholar] [CrossRef]
  198. Iwasaki, A.; Ohno, O.; Sumimoto, S.; Ogawa, H.; Nguyen, K.A.; Suenaga, K. Jahanyne, an apoptosis-inducing lipopeptide from the marine cyanobacterium Lyngbya sp. Org. Lett. 2015, 17, 652–655. [Google Scholar] [CrossRef]
  199. Iwasaki, A.; Fujimura, H.; Okamoto, S.; Kudo, T.; Hoshina, S.; Sumimoto, S.; Teruya, T.; Suenaga, K. Isolation of jahanene and jahanane, and total synthesis of the jahanyne family. J. Org. Chem. 2018, 83, 9592–9603. [Google Scholar] [CrossRef]
  200. Inuzuka, T.; Yamamoto, K.; Iwasaki, A.; Ohno, O.; Suenaga, K.; Kawazoe, Y.; Uemura, D. An inhibitor of the adipogenic differentiation of 3T3-L1 cells, yoshinone A, and its analogs, isolated from the marine cyanobacterium Leptolyngbya sp. Tetrahedron Lett. 2014, 55, 6711–6714. [Google Scholar] [CrossRef]
  201. Cui, J.; Morita, M.; Ohno, O.; Kimura, T.; Teruya, T.; Watanabe, T.; Suenaga, K.; Shibasaki, M. Leptolyngbyolides, cytotoxic macrolides from the marine cyanobacterium Leptolyngbya sp.: Isolation, biological activity, and catalytic asymmetric total synthesis. Chem. A Eur. J. 2017, 23, 8500–8509. [Google Scholar] [CrossRef]
  202. Dai, L.; Chen, B.; Lei, H.; Wang, Z.; Liu, Y.; Xu, Z.; Ye, T. Total synthesis and stereochemical revision of lagunamide A. Chem. Commun. 2012, 48, 8697–8699. [Google Scholar] [CrossRef] [Green Version]
  203. Tripathi, A.; Puddick, J.; Prinsep, M.R.; Rottmann, M.; Tan, L.T. Lagunamides A and B: Cytotoxic and antimalarial cyclodepsipeptides from the marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2010, 73, 1810–1814. [Google Scholar] [CrossRef]
  204. White, J.D.; Xu, Q.; Lee, C.-S.; Valeriote, F.A. Total synthesis and biological evaluation of (+)-kalkitoxin, a cytotoxic metabolite of the cyanobacterium Lyngbya majuscula. Org. Biomol. Chem. 2004, 2, 2092–2102. [Google Scholar] [CrossRef]
  205. Li, W.I.; Berman, F.W.; Okino, T.; Yokokawa, F.; Shioiri, T.; Gerwick, W.H.; Murray, T.F. Antillatoxin is a marine cyanobacterial toxin that potently activates voltage-gated sodium channels. Proc. Natl. Acad. Sci. USA 2001, 98, 7599–7604. [Google Scholar] [CrossRef] [Green Version]
  206. Nguyen, V.-A.; Willis, C.L.; Gerwick, W.H. Synthesis of the marine natural product barbamide. Chem. Commun. 2001, 1934–1935. [Google Scholar] [CrossRef]
  207. Orjala, J.; Gerwick, W.H. Barbamide, a chlorinated metabolite with molluscicidal activity from the Caribbean cyanobacterium Lyngbya majuscula. J. Nat. Prod. 1996, 59, 427–430. [Google Scholar] [CrossRef] [PubMed]
  208. Pirovani, R.; Brito, G.; Barcelos, R.; Pilli, R. Enantioselective Total Synthesis of (+)-Lyngbyabellin M. Mar. Drugs 2015, 13, 3309–3324. [Google Scholar] [CrossRef] [Green Version]
  209. Choi, H.; Mevers, E.; Byrum, T.; Valeriote, F.A.; Gerwick, W.H. Lyngbyabellins K–N from two Palmyra atoll collections of the marine cyanobacterium Moorea bouillonii. Eur. J. Org. Chem. 2012, 2012, 5141–5150. [Google Scholar] [CrossRef] [PubMed]
  210. Ojima, D.; Iwasaki, A.; Suenaga, K. Total synthesis of kanamienamide and clarification of biological activity. J. Org. Chem. 2017, 82, 12503–12510. [Google Scholar] [CrossRef] [PubMed]
  211. Ogawa, H.; Iwasaki, A.; Sumimoto, S.; Kanamori, Y.; Ohno, O.; Iwatsuki, M.; Ishiyama, A.; Hokari, R.; Otoguro, K.; Ōmura, S.; et al. Janadolide, a cyclic polyketide–peptide hybrid possessing a tert-butyl group from an Okeania sp. marine cyanobacterium. J. Nat. Prod. 2016, 79, 1862–1866. [Google Scholar] [CrossRef]
  212. Sueyoshi, K.; Kaneda, M.; Sumimoto, S.; Oishi, S.; Fujii, N.; Suenaga, K.; Teruya, T.J.T. Odoamide, a cytotoxic cyclodepsipeptide from the marine cyanobacterium Okeania sp. Tetrahedron 2016, 72, 5472–5478. [Google Scholar] [CrossRef]
  213. Sun, T.; Zhang, W.; Zong, C.; Wang, P.; Li, Y. Total synthesis and stereochemical reassignment of tasiamide B. J. Peptide Sci. 2010, 16, 364–374. [Google Scholar] [CrossRef] [PubMed]
  214. Gunasekera, S.P.; Li, Y.; Ratnayake, R.; Luo, D.; Lo, J.; Reibenspies, J.H.; Xu, Z.; Clare-Salzler, M.J.; Ye, T.; Paul, V.J. Discovery, total synthesis and key structural elements for the immunosuppressive activity of cocosolide, a symmetrical glycosylated macrolide dimer from marine cyanobacteria. Chemistry 2016, 22, 8158–8166. [Google Scholar] [CrossRef] [Green Version]
  215. Namikoshi, M.; Murakami, T.; Fujiwara, T.; Nagai, H.; Niki, T.; Harigaya, E.; Watanabe, M.F.; Oda, T.; Yamada, J.; Tsujimura, S. Biosynthesis and transformation of homoanatoxin-a in the cyanobacterium Raphidiopsis mediterranea Skuja and structures of three new homologues. Chem. Res. Toxicol. 2004, 17, 1692–1696. [Google Scholar] [CrossRef]
  216. Carneiro, V.M.; Avila, C.M.; Balunas, M.J.; Gerwick, W.H.; Pilli, R.A. Coibacins A and B: Total synthesis and stereochemical revision. J. Org. Chem. 2014, 79, 630–642. [Google Scholar] [CrossRef] [Green Version]
  217. Balunas, M.J.; Grosso, M.F.; Villa, F.A.; Engene, N.; McPhail, K.L.; Tidgewell, K.; Pineda, L.M.; Gerwick, L.; Spadafora, C.; Kyle, D.E. Coibacins A–D, antileishmanial marine cyanobacterial polyketides with intriguing biosynthetic origins. J. Nat. Prod. 2012, 14, 3878–3881. [Google Scholar] [CrossRef] [PubMed]
  218. Ojima, D.; Yasui, A.; Tohyama, K.; Tokuzumi, K.; Toriihara, E.; Ito, K.; Iwasaki, A.; Tomura, T.; Ojika, M.; Suenaga, K. Total Synthesis of Miuraenamides A and D. J. Org. Chem. 2016, 81, 9886–9894. [Google Scholar] [CrossRef]
  219. Wang, D.; Song, S.; Tian, Y.; Xu, Y.; Miao, Z.; Zhang, A. Total synthesis of the marine cyclic depsipeptide viequeamide A. J. Nat. Prod. 2013, 76, 974–978. [Google Scholar] [CrossRef] [PubMed]
  220. Boudreau, P.D.; Byrum, T.; Liu, W.-T.; Dorrestein, P.C.; Gerwick, W.H. Viequeamide A, a cytotoxic member of the kulolide superfamily of cyclic depsipeptides from a marine button cyanobacterium. J. Nat. Prod. 2012, 75, 1560–1570. [Google Scholar] [CrossRef] [Green Version]
  221. Lemmens-Gruber, R.; Kamyar, M.R.; Dornetshuber, R. Cyclodepsipeptides-potential drugs and lead compounds in the drug development process. Curr. Med. Chem. 2009, 16, 1122–1137. [Google Scholar] [CrossRef]
  222. Kitagaki, J.; Shi, G.; Miyauchi, S.; Murakami, S.; Yang, Y. Cyclic depsipeptides as potential cancer therapeutics. Anti Cancer Drugs 2015, 26, 259–271. [Google Scholar] [CrossRef] [PubMed]
  223. Siow, A.; Opiyo, G.; Kavianinia, I.; Li, F.F.; Furkert, D.P.; Harris, P.W.R.; Brimble, M.A. Total synthesis of the highly N-methylated acetylene-containing anticancer peptide jahanyne. Org. Lett. 2018, 20, 788–791. [Google Scholar] [CrossRef] [PubMed]
  224. Kunifuda, K.; Iwasaki, A.; Nagamoto, M.; Suenaga, K. Total synthesis and absolute configuration of koshikalide. Tetrahedron Lett. 2016, 57, 3121–3123. [Google Scholar] [CrossRef]
  225. Shen, B. Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Curr. Opin. Chem. Biol. 2003, 7, 285–295. [Google Scholar] [CrossRef]
  226. Staunton, J.; Weissman, K.J. Polyketide biosynthesis: A millennium review. Nat. Prod. Rep. 2001, 18, 380–416. [Google Scholar] [CrossRef] [PubMed]
  227. Ojima, D.; Mine, H.; Iwasaki, A.; Suenaga, K. Total synthesis of janadolide. Tetrahedron Lett. 2018, 59, 1360–1362. [Google Scholar] [CrossRef]
  228. Iwasaki, A.; Ohno, O.; Sumimoto, S.; Suda, S.; Suenaga, K. Kurahyne, an acetylene-containing lipopeptide from a marine cyanobacterial assemblage of Lyngbya sp. RSC Adv. 2014, 4, 12840–12843. [Google Scholar] [CrossRef] [Green Version]
  229. Sansone, C.; Brunet, C.; Noonan, D.M.; Albini, A. Marine algal antioxidants as potential vectors for controlling viral diseases. Antioxidants 2020, 9, 392. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Antioxidant and antiobesity compounds from cyanobacteria.
Figure 1. Antioxidant and antiobesity compounds from cyanobacteria.
Marinedrugs 19 00241 g001
Figure 2. Cytotoxic compounds form Nostoc sp.
Figure 2. Cytotoxic compounds form Nostoc sp.
Marinedrugs 19 00241 g002
Figure 3. Cytotoxic compounds form Moorea producens.
Figure 3. Cytotoxic compounds form Moorea producens.
Marinedrugs 19 00241 g003
Figure 4. Cytotoxic cyanobacteria-derived metabolites.
Figure 4. Cytotoxic cyanobacteria-derived metabolites.
Marinedrugs 19 00241 g004
Figure 5. Antiparasite metabolites from cyanobacteria.
Figure 5. Antiparasite metabolites from cyanobacteria.
Marinedrugs 19 00241 g005
Figure 6. The structures of the cyanobacterial metabolites as drug leads against SARS-CoV-2, (a) the sequence of amino acids in 40, (b) Antillatoxin (41), (c) Curacin A (42), (d) Cryptophycin 52 (43).
Figure 6. The structures of the cyanobacterial metabolites as drug leads against SARS-CoV-2, (a) the sequence of amino acids in 40, (b) Antillatoxin (41), (c) Curacin A (42), (d) Cryptophycin 52 (43).
Marinedrugs 19 00241 g006
Figure 7. Clinically tested compounds and approved drugs from marine cyanobacteria.
Figure 7. Clinically tested compounds and approved drugs from marine cyanobacteria.
Marinedrugs 19 00241 g007
Figure 8. Biotechnological applications of cyanobacteria.
Figure 8. Biotechnological applications of cyanobacteria.
Marinedrugs 19 00241 g008
Figure 9. Applications of marine cyanobacteria in nanobiotechnology.
Figure 9. Applications of marine cyanobacteria in nanobiotechnology.
Marinedrugs 19 00241 g009
Figure 10. Marine cyanobacterial derived compounds suggested to be tested as nanoparticles.
Figure 10. Marine cyanobacterial derived compounds suggested to be tested as nanoparticles.
Marinedrugs 19 00241 g010
Figure 11. Structures of synthesized compounds (5870) isolated from marine cyanobacteria.
Figure 11. Structures of synthesized compounds (5870) isolated from marine cyanobacteria.
Marinedrugs 19 00241 g011
Figure 12. Structures of synthesized compounds (7183) isolated from marine cyanobacteria.
Figure 12. Structures of synthesized compounds (7183) isolated from marine cyanobacteria.
Marinedrugs 19 00241 g012
Scheme 1. Total Synthesis of jahanyne.
Scheme 1. Total Synthesis of jahanyne.
Marinedrugs 19 00241 sch001aMarinedrugs 19 00241 sch001b
Scheme 2. Retrosynthetic analysis and total synthesis of janadolide.
Scheme 2. Retrosynthetic analysis and total synthesis of janadolide.
Marinedrugs 19 00241 sch002
Table 1. Cyanobacterial derived natural products used in clinical tests.
Table 1. Cyanobacterial derived natural products used in clinical tests.
Compound Name (No.)/Chemical ClassCyanobacteria Species/SourceType of ActivityClinical Status/Study TypeReferences
Dolastatin 10 (44)/DepsipeptidesSymploca sp.Sarcoma, Leukemia, Lymphoma, Liver Cancer, and Kidney Cancer, among others.Drug
Investigational
[92,93,94,95,96,97,98,99,100]
Leukemia
Lymphoma
Drug Intervention
Phase II
Prostate CancerDrug Intervention
Phase II
Kidney CancerDrug Intervention
Phase II
Extrahepatic Bile Duct Cancer
Gallbladder Cancer
Liver Cancer
Drug Intervention
Phase II
Ovarian Cancer
Sarcoma
Drug Intervention
Phase I
Leukemia
Myelodysplastic Syndromes
Drug Intervention
Phase I
Pancreatic CancerDrug
Phase II Intervention
Cemadotin (47), Tasidotin (48) and Synthadotin (49) (Derived from dolastatin 15 (45)/DepsipeptideDolabella auricularia and cyanobacteria Symploca (later)MelanomaDrug: ILX651
Intervention
Phase II
Hormone-refractory Prostate Cancer[101,102,103,104]
Non-Small-Cell Lung Carcinoma
Cryptophycin 52 (43)/(Synthetic analog of cryptophycin 1 (5) DepsipeptidesNostoc sp., terrestrial cyanobacteriaSchizophreniaCognitive remediation therapy, Intervention
Not Applicable Phase
[101,105,106]
Hypertension
Metabolic Disorder
Drug: losartan potassium (+) hydrochlorothiazide, Intervention
Phase III
Toyocamycin (52)/Pyrrolopyrimidine nucleosideStreptomyces toyocaensis
Cyanobacteria
Non-Small-Cell Lung CarcinomaDrug
Experimental
[101,107]
Phytoalexin (53)/PolysaccharidesScytonema ocellatumType 2 Diabetes (RED)Drug
Phase I Intervention
[108,109]
Soblidotin (46)/(Synthetic analog of dolastatin 10) Depsipeptides SarcomaDrug
Intervention
Phase II
[101,110]
Lung Cancer
Phycocyanin (54)/A pigment-protein complexSpirulinaChronic PeriodontitisDrug: Spirulina capsules, Intervention
Phase IV
[111,112,113]
Metabolic SyndromeDietary Supplement: Spirulysat®
Dietary Supplement: Placebo
Intervention
Not Applicable Phase
Anatoxins-a (51)/ PeptidesAnabeana circinalisAmyotrophic Lateral SclerosisRecruiting
Patient Registry
Intervention
[114,115]
Bacteriocins/Peptides43 different cyanobacteria viz., Prochlorcoccus marinus, Synechococcus sp., Cyanothece sp., Microcystis aeruginosa, Synechocystis, Arthospira, Nostoc, Anabaena, NodulariaVentilator Associated PneumoniaLactobacillus bacteria
Intervention
[116,117,118,119,120]
Colic, Infantile
Probiotic
Gut Microbiome
Bifidobacterium Breve
Drug
Intervention
Phase IV
HealthyPlantaricin A—rejuvenating cream, antioxidant serum, rejuvenating serum
Intervention
Phase III
White Spot Lesion of Tooth
Long Term Adverse Effects
Caries, Dental
Orthodontic Appliance Complication
Drug: Probiotic Toothpaste
Drug: Dr. Reddy’s Clohex
Other: Control Group
Intervention
Phase I and II
Curacin (50)/LipopeptidesLyngbya majuscule In vivo animal trails.
Preclinical
Phase (but it served as a lead compound)
[91]
Cyanovirin-N (40) (CVN)/A proteinNostoc ellipsosporumInhibiting HIV cell entry in a highly specific manner.Preclinical
Phase
[121]
Table 2. List of synthesized compounds isolated from marine cyanobacteria sources and their activities.
Table 2. List of synthesized compounds isolated from marine cyanobacteria sources and their activities.
Marine SourceCompound Name/ClassRegion/YearBiological ActivityReferences
Marine cyanobacteriumHoshinolactam (58) The coast near
Hoshino, Okinawa/2017
Antitrypanosomal
activity, IC50 = 3.9 (Syn.), 6.1 (Nat.) nM. Cytotoxicity against MRC-5 cells IC50 > 25 μM (Syn. and Nat.)
PC = pentamidinea NC = not
(in vitro)
[189]
Lyngbya sp.Koshikalide (59)Koshika, Shima City, Mie prefecture/2010Cytotoxicity against HeLa S3 cells, IC50 = 42 µg/mL.
PC = not
NC = not
(in vitro)
[190]
Lyngbya majuscule.Apratoxin A (22)/CyclodepsipeptideFinger’s Reef, Apra Harbor, Guam/2001Cytotoxicity against KB (IC50 = 0.52 nM) and LoVo cancer cells (IC50 = 0.36 nM).
(in vitro)
Against a colon tumor and ineffective against a mammary tumor.
(in vivo)
[191,192]
Lyngbya sp. & Lyngbya confervoides./Lyngbyastatin 7 (60)/Lariat-type cyclic depsipeptideMangrove channel, Kemp Channel, at the northern end of Summerland Key, Florida Keys/2005Blocking elastase activity, IC50 = 70 nM, antiproliferation and abrogating the elastase-triggered induction of proinflammatory cytokine expression.
PC = sivelestat, or (DMSO)
NC = NR
(in vivo)
[193,194]
Lyngbya bouillonii(−)-Lyngbyaloside B (61)/Glycoside macrolideUlong Channel, Palau/2000Cytotoxicity against KB cells, IC50 = 4.3 µM and LoVo cells, IC50 = 15 µM.[195,196]
Lyngbya sp.Maedamide (62)/Acyclic peptideKuraha, Okinawa/2014Inhibitory
activity against chymotrypsin, IC50 = 45 μM, HeLa and HL60 cells, IC50 = 4.2 and 2.2 μM.
[197]
Lyngbya sp.Jahanyne (63)/LipopeptidesThe coast near Jahana, Okinawa, Japan/2015Cytotoxicity against HeLa cells and HL60 cells, IC50 = 1.8 μM and 0.63 μM (et al., 2015) natural jahanyne, IC50 = (22 ± 2, 4.6 ± 1.2 μM) and synthetic (21 ± 2, 8.3 ± 2.3 μM).[198,199]
Leptolyngbya sp.Yoshinone A (64)Ishigaki island, Okinawa, Japan/2014Antiobesity activity (in vivo) in mice, (Inhibited differentiation of 3T3-L1 cells into adipocytes, EC50 = 420 nM) and toxicity against Saccharomyces cerevisiae ABC16-Monster, (IC50 = 63.8 µM).[200]
Leptolyngbyolide C (65)/MacrolideOn the coast of Itoman City, Okinawa, Japan/2007 Growth-inhibitory
activity against HeLa S3 cells, (IC50 = 0.64 µg mL−1) and depolymerization of F-actin (EC50 = 26.9 µg mL−1).
(in vitro)
[201]
Lyngbya majusculaLagunamide A (66)/CyclodepsipeptideWestern lagoon of Pulau Hantu Besar, Singapore/June 2007Antimalarial activity against Plasmodium falciparum, IC50 = 0.19 and cytotoxic activity against P388 murine leukemia cell lines, IC50 = 6.4 nM, and moderate antiswarming activities against
Pseudomonas aeruginosa PA01.
PC: MeOH-treated plate
[202,203]
Lyngbya majuscula(−)-kalkitoxin (67)Curaçao/2004Cytotoxicity against the human colon cell line HCT-116, IC50 = 1.0 × 10−3 μg mL−1, inhibited hypoxia-induced activation of HIF-1 in T47D breast tumor cells (IC50 = 5.6 nM) [204]
Lyngbya majusculaAntillatoxin (41)/Cyclic lipodepsipeptideCuracüao/2005Strong ichthyotoxicity and neurotoxicity
(EC50 = 20.1 ± 6.4 nM).
[187,205]
Lyngbya majuscula & Schizothrix sp.Somamide A (68)/Macrocyclic depsipeptideFijian Island/2005 [187]
Lyngbya majusculaBarbamide (69)/LipopeptideCuracüao/1996Potent molluscicidal activity against Biomphalaria glabrata, LC100 = 100 µg/mL[206,207]
Moorea bouillonii(+)-Lyngbyabellin M (70)/LipopeptideNorth lagoon at Strawn Island, Palmyra Atoll, USA/August 2009Not reported[208,209]
Kanamienamide (71)The shore of Kanami, Kagoshima, Japan/2016Growth-inhibitory activity.
As a necrosislike cell death inducer.
[210]
Okeania sp.Janadolide (72)/Cyclic polyketide- peptideBise, Okinawa Prefecture, Japan/2016Antitrypanosomal activity without cytotoxicity against human cells (IC50 47 nM)[211]
Kurahyne (73) (N-Me)
Kurahyne B (74) (N-H)
The coast near Jahana, Okinawa/March 2013Growth-inhibitory activity
(Inhibited the growth of both HeLa and HL60 cells, IC50 = 8.1 and 9.0 μM)
PC = Adriamycin
[186]
Odoamide (75)/CyclodepsipeptideOdo, Okinawa Prefecture, Japan/May 2009(in vitro)
Cytotoxicity against
HeLa S3 cells, IC50 = 26.3 nM.
Toxicity against brine shrimp (Artemia), LD50 = 1.2 µM.
[212]
Symploca sp.Tasiamide B (76)/Acyclic peptideMicronesia by Moore et al., 2003Cytotoxic against KB cells, IC50 = 0.8 µM[213]
Cocosolide (77)/Glycosylated macrolideCocos Lagoon and Tanguisson reef flat, Guam/2016Inhibited IL-2 production in both T-cell receptors also suppressed the proliferation of anti-CD3-stimulated T-cells in a dose-dependent manner.
(IC50 > 50 mm).
[214]
Oscillatoria FormosaHomoanatoxin-a (78)Inniscarra
reservoir, County Cork, Ireland/2004
Cytotoxic activity
LD50’s in mice of 200–250 µg/kg.
[215]
Oscillatoria sp.Coibacin A (79)/Unsaturated polyketide lactonePanamanian/2012Antileishmanial activity against axenic amastigotes of Leishmania donovani (IC50 = 2.4 μM). Cytotoxicity against NCI-H460 cells (IC50 = 31.5 μM).
Antiinflammatory activity by cell-based nitric oxide (NO) (IC50 = 20 μM).
[216,217]
Coibacin B (80)/Unsaturated polyketide lactone As a leishmanicidal drug (IC50 = 7.2 μM); cytotoxicity against human cancer lung cell lines (NCI-H460), IC50 = 17.0 μM. Active coibacin representative (IC50 = 5 μM).
Paraliomixa miuraensisMiuraenamide A (81) (R1 = Ph, R2 = O Me)
Miuraenamide D (82) (R1 = O Me, R2= Ph)/Cyclodepsipeptides
The seashore on Miura Peninsula in Kanagawa, Japan by Ojika et al., 2006Cytotoxicity against HeLa cells, IC50 = A (0.031), D (0.021) μM.
Against HeLa-S3 cell line, IC50 = A (0.38), D (1.32) μM.
antiphytophthora activity 3, 30 ng/disk
[218]
Rivularia sp. “button” Marine cyanobacteriumViequeamide A (83)/Cyclic depsipeptideNear the island of Vieques, Puerto Rico/2012Highly toxic against H460 human lung cancer cell lines, IC50 = 60 nm.
PC = paclitaxel (3.2 nM) and etoposide (63.1 nM)
[219,220]
PC (positive control) and NC (negative control).
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Khalifa, S.A.M.; Shedid, E.S.; Saied, E.M.; Jassbi, A.R.; Jamebozorgi, F.H.; Rateb, M.E.; Du, M.; Abdel-Daim, M.M.; Kai, G.-Y.; Al-Hammady, M.A.M.; et al. Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications. Mar. Drugs 2021, 19, 241. https://doi.org/10.3390/md19050241

AMA Style

Khalifa SAM, Shedid ES, Saied EM, Jassbi AR, Jamebozorgi FH, Rateb ME, Du M, Abdel-Daim MM, Kai G-Y, Al-Hammady MAM, et al. Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications. Marine Drugs. 2021; 19(5):241. https://doi.org/10.3390/md19050241

Chicago/Turabian Style

Khalifa, Shaden A. M., Eslam S. Shedid, Essa M. Saied, Amir Reza Jassbi, Fatemeh H. Jamebozorgi, Mostafa E. Rateb, Ming Du, Mohamed M. Abdel-Daim, Guo-Yin Kai, Montaser A. M. Al-Hammady, and et al. 2021. "Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications" Marine Drugs 19, no. 5: 241. https://doi.org/10.3390/md19050241

APA Style

Khalifa, S. A. M., Shedid, E. S., Saied, E. M., Jassbi, A. R., Jamebozorgi, F. H., Rateb, M. E., Du, M., Abdel-Daim, M. M., Kai, G. -Y., Al-Hammady, M. A. M., Xiao, J., Guo, Z., & El-Seedi, H. R. (2021). Cyanobacteria—From the Oceans to the Potential Biotechnological and Biomedical Applications. Marine Drugs, 19(5), 241. https://doi.org/10.3390/md19050241

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop