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Review

The Tetrahydrofuran Motif in Marine Lipids and Terpenes

by
Paula González-Andrés
1,
Laura Fernández-Peña
1,
Carlos Díez-Poza
2,* and
Asunción Barbero
1,*
1
Department of Organic Chemistry, Campus Miguel Delibes, University of Valladolid, 47011 Valladolid, Spain
2
Departamento de Química Orgánica y Química Inorgánica, Facultad de Farmacia e Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá, Ctra. Madrid-Barcelona, 28871 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2022, 20(10), 642; https://doi.org/10.3390/md20100642
Submission received: 20 September 2022 / Revised: 9 October 2022 / Accepted: 12 October 2022 / Published: 15 October 2022
(This article belongs to the Special Issue Heterocyclic Compounds from Marine Organisms)
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Abstract

:
Heterocycles are particularly common moieties within marine natural products. Specifically, tetrahydrofuranyl rings are present in a variety of compounds which present complex structures and interesting biological activities. Focusing on terpenoids, a high number of tetrahydrofuran-containing metabolites have been isolated during the last decades. They show promising biological activities, making them potential leads for novel antibiotics, antikinetoplastid drugs, amoebicidal substances, or anticancer drugs. Thus, they have attracted the attention of the synthetics community and numerous approaches to their total syntheses have appeared. Here, we offer the reader an overview of marine-derived terpenoids and related compounds, their isolation, structure determination, and a special focus on their total syntheses and biological profiles.

Graphical Abstract

1. Introduction

Marine organisms are a source of intriguing and fascinating compounds. These living beings have continuously evolved over time, since they are part of the oldest habitat on earth. Being also the largest ecosystem, the ocean has the potential to offer innumerable compounds with interesting biological activities yet to be discovered [1]. This is supported by the fact that hundreds of new molecules are reported within the scientific community every year [2,3,4].
Usually, the isolation of pure active compounds is a time-consuming and expensive process, due to the need of efficient extraction processes and sequential purification steps. Moreover, large amounts of raw materials have to be collected to finally isolate fairly low quantities of the desired compounds.
Fortunately, the great contribution of chemists in the field of total synthesis and asymmetric catalysis over the last decades has had countless benefits. On one hand, even though nuclear magnetic resonance (NMR) techniques are very powerful tools, in some cases, the characterization of complex molecules can be difficult, leading to misassignments [5]. Fortunately, total synthesis has emerged as a—somewhat—costly but effective tool for the determination of the absolute configuration of marine metabolites. On the other hand, synthesis provides access to sufficient quantities of the desired compounds for further extensive biological studies.
Within the marine-derived metabolites, terpenes represent one of the most significant families. They are a large and diverse group of compounds that usually present valuable pharmacological properties. Various reviews summarize the discovery of a high number of these metabolites in recent years from different sources, namely sponges [6,7], fungi [8,9,10], and corals [11,12], among others [13,14].
Other common structural motifs present in marine drugs are heterocycles. Within them, five-, six-, and seven-membered oxygenated heterocycles are frequently found in such bioactive compounds. The six-membered tetrahydropyrans, the most abundant, are common targets of study [15,16]. The corresponding seven-membered oxepanes, and their appearance in relevant bioactive marine compounds, were reviewed by our group [17]. Regarding tetrahydrofurans, Fernandes and coworkers recently reviewed the most iconic examples of total synthesis of 2,3,5-trisubstituted tetrahydrofuran-containing natural products [18,19]. We have also recently summarized the synthesis and biological properties of marine-derived tetrahydrofuran-containing compounds, focusing on the polyketide family [20].
Continuing our series, here we give an overview of tetrahydrofuran-containing marine drugs, focusing on the terpene family and related compounds. We searched SciFinder for tetrahydrofuran-containing compounds with biological activity, focusing on the period 2000–2022. Our search was refined to compounds of the terpenoid family of compounds of marine origin, finding 81 compounds (Table 1). The main source (see Figure 1) was algae (32 compounds), followed by sponges (19 compounds), fungi (15 compounds), lampreys (6), bacteria (5), and corals (4). Excluding nonterpenoid lipids, we found 55 terpenoid compounds (see Figure 2), most of them being triterpenes (23) followed by meroterpenes (14), monoterpenes (9), diterpenes (5) and, finally, sesquiterpenes (4).
We want to offer the reader an overview of the most recent tetrahydrofuran-containing terpenoids and related compounds of marine origin, their natural source of isolation, biological properties, and synthetic strategies towards them. We have also included classic examples, as their structure and activity are closely related to the more recently isolated metabolites and help to understand structure–activity relationships. We start with some examples of fatty acids with interesting biological profiles, and then move to the broad family of terpenoid compounds (monoterpenes, sesquiterpenes, diterpenes, triterpenes, and meroterpenoids). At the end, we also highlight other small THF-containing compounds that show interesting biological activities or were recently isolated and, thus, have potential to be shown in the near future.

2. Lipids

2.1. Lipid Alcohols

C19 Lipid Diols

Diastereomeric trans-oxylipids 1, and cis-oxylipid 2 (Figure 3), were isolated in 1980 [21] and 1998 [22], respectively, from the brown alga Notheia anomala. Their structure and relative stereochemistry were assigned by 1D and 2D NMR spectral data and confirmed by single-crystal X-ray analysis. Their absolute configuration was determined by the Horeau method in the case of compound 1, and by the advanced Mosher method for compound 2. Both of them display in vitro antihelmintic activity, inhibiting larval development in parasitic nematodes. The trans-isomer 1 showed LD50 values against Haemonchus contortus (1.8 ppm) and Trichostrongylus colubriformis (9.9 ppm), comparable to those of the commercial nematocides levamisole and closantel. Synthetic routes for these oxylipids were recently reviewed [18].
An elegant example of the stereodivergent synthesis of both isomers was developed by Kim et al. [23]. They developed an intramolecular amide enolate alkylation, where the C3-hydroxy protecting group selection permits the formation of the desired isomer (Scheme 1). Thus, starting from PMB-protected bromoamide 3, reaction with LiHMDS afforded only the cis-product 4. The preferent formation of the cis-isomer was due to the chelating ability of the PMB group. Therefore, when using a nonchelating group such as TIPS (compound 5), the reaction with KHMDS predominantly yielded the trans-THF 6. Further reaction of 4 and 6 with CH2=CH(CH2)7MgBr and reduction with L-selectride afforded 7 and 8 in good yields (76% and 53% over two steps, respectively). Deprotection of 7 with DDQ, and 8 with TBAF, respectively, gave cis-oxylipid 2 in 82% yield and the trans-isomer 1 in 94% yield.

2.2. Fatty Acids

2.2.1. Petromyroxols

In 2015, Li reported the isolation of (+)- and (−)-petromyroxols (9) [24]. They are oxylipids isolated from water conditioned with larval sea lamprey Petromyzon marinus L. Interestingly, these molecules are the first tetrahydrofuran acetogenindiols isolated from a vertebrate animal (Figure 4). The absolute configuration of each enantiomer was determined by a combination of Mosher ester analysis and comparison with related natural and synthetic products. The (+)-9 shows a potent olfactory response of 0.01 to 1 μM in the sea lamprey, while the (−)-isomer has a softer effect. Synthetic routes towards them were recently reviewed [18].
A recent example of the synthesis of (+)-9, along with all possible diastereoisomers, was presented in 2020 by Ramana and coworkers [25]. The synthetic route started from the commercial THF compound 10 (Scheme 2). The alkyl chain was installed by reaction with the appropriate cuprate. Subsequent benzyl protection of 11 afforded 12, which after reaction with allyltrimethylsilane, yielded the desired diastereomer (7:2 ratio) of the allylated THF 13. After protection with a para-nitrobenzoate (PNB) group under Mitsunobu conditions, compound 14 was subjected to oxidative olefin cleavage with OsO4/NaIO4 and subsequent Wittig olefination to obtain a-b-unsaturated ester 15. Hydrogenation with Pearlman catalyst (20% Pd(OH)2/C) afforded 16 in 89% yield, where the benzyl group, the double bond, and the nitro group were all reduced. Finally, hydrolysis of both ester groups with KOH in methanol afforded the desired (+)-petromyroxol in 77% yield.

2.2.2. PMA

Petromyric acids A and B (PMA and PMB) are dehydroxylated tetrahydrofuranyl fatty acids that were isolated from larval washing extracts from the sea lamprey Petromyzon marinus in 2018 [26]. From the washing extract, four fatty acids related to the acetogenin family were identified: (+)-PMA ((+)-17), (−)-PMA ((−)-17), (+)-PMB ((+)-18), and (−)-PMB ((−)-18) (Figure 5). Their chemical structure was elucidated by NMR spectroscopy and confirmed by chemical synthesis and X-ray crystallography.
Sea lampreys are anadromous fishes that migrate, using their olfactory cues to orientate, from the ocean to freshwater to find a suitable spawning stream. When approaching river mouths, the decision of which stream is optimal to spawn in is taken using their olfactory system to detect a pheromone emitted from larval sea lampreys. When investigating larval washing extracts, four fatty acids were identified, but only (+)-17 has proven to be the pheromone that guides lamprey adults. However, its enantiomer, (−)-17, does not produce the same behavioral effect. Fatty acid analogues have been reported to be pheromones in insects, but this is the first identification in fish. The sea lamprey is a destructive invader in the Laurentian Great Lakes, while in Europe, its population has decreased precipitously, so (+)-17 can be used for the control and conservation of their populations.
Although they have a high potential for application, to the best of our knowledge, no total synthesis has been reported so far for these compounds.

2.2.3. Mutafurans

Mutafurans A–G (19–25) are brominated ene-ynetetrahydrofurans (Figure 6) that were isolated by Molinski in 2007 from the marine sponge Xextospongia muta [27]. Later, Liu reported the isolation of mutafuran H (26), a brominated ene-tetrahydrofuran isolated from sponge Xextospongia testudinaria within other sterols and brominated compounds [28]. Their structure and absolute configuration were determined by 1D and 2D magnetic resonance, mass spectrometry, and circular dichroism.
Mutafurans A–D showed moderate antifungal activity against the fungus Cryptococcus neoformans var. grubii, but were inactive against Candida albicans (ATCC14503 and 96–489) and Candida glabrata [27]. Furthermore, mutafuran H showed biological activity against Artemia salina larvae (LC50 = 2.6 μM) and a significant acetylcholinesterase inhibitory activity (IC50 = 0.64 μM) [28]. No synthetic approach has been reported to date.

2.2.4. Aspericacids

Aspericacids A (27) and B (28) were isolated in 2020 by Ding and He from the sponge-associated Aspergillus sp. LS78 [29]. Both compounds bear a 2,5-disubstituted tetrahydrofuran ring coupled with an unsaturated fatty acid (Figure 7). Their structure was determined by HRESIMS and 1D and 2D NMR spectroscopy, while their absolute configuration was established relying on electronic circular dichroism (ECD). Compound 27 presents a moderate inhibitory activity against Candida albicans and Cryptococcus neoformans with a MIC value of 50 μg/mL, although 28 has a weaker activity, MIC = 128 μg/mL. No synthetic approach has been reported to date.

3. Terpenes

3.1. Monoterpenes

3.1.1. Pantofuranoids

Pantofuranoids A–F (29–34) are monoterpenes that were isolated in 1996 from the Antarctic red alga Pantoneura plocamioides [30]. They are the first monoterpenes found to contain a tetrahydrofuran moiety, and their common framework (Figure 8) suggests that they all come from the same terpene precursor.
In 2006, Toste reported the enantioselective total synthesis of (−)-33, in which the key step is a vanadium-catalyzed sequential resolution/oxidative cyclization [31]. Using an in situ generated vanadium(V)–oxo complex with chiral tridentate Schiff base ligand 35 as catalyst, racemic homoallylic alcohol 36 was readily converted into 2,4-cis-substituted THF 37 (Scheme 3). The observed stereochemistry can be explained through a chair-like transition state in which coordination of the pseudo-equatorial ester group to the vanadium complex determines the selectivity of the syn-epoxidation step. Then, compound 37 was further elaborated to (−)-33 in 6 steps and 29% overall yield from 37.

3.1.2. Furoplocamioids

Furoplocamioids A–C 38–40 (Figure 9) are monoterpenes that were isolated in 2001 from the red marine alga Plocamium cartilagineum [32]. They bear an unusual polyhalogenated tetrahydrofuranyl ring. Their structural similarity to pantofuranoids suggests a close relationship between the species that produce them. This is an interesting fact, since Plocamium cartilagineum and Pantoneura plocamioides are classified in different orders, Gigartinales and Ceramiales. Therefore, a taxonomic revision could be required. Later, the Darias group determined the C7 relative stereochemistry by comparison with the NMR spectra of similar reported terpenes [33]. González-Coloma and coworkers found that 38 and 40 show antifeedant effects against Leptinotarsa decemlineata. It was shown that 40 was also an efficient aphid repellent (against Mizuspersicae and Ropalosiphumpadi) and selective insect cell toxicant. In addition, both compounds showed low mammalian toxicity and phytotoxic effects [34].

3.2. Sesquiterpenes

3.2.1. Heronapyrrols

Heronapyrrols A–C are pyrroloterpenes that were isolated in 2010 from a marine Streptomyces sp. CMB-M0423 [35]. They present bioactivity against Gram-positive bacteria Staphylococcus aureus ATCC 9144 and Bacillus subtilis ATCC 6633 but no mammalian cytotoxicity. Heronapyrrol C (41), apart from the characteristic and unusual 2-nitropyrrol moiety of this family, presents a bis-tetrahydrofuran core. Later, Capon and Stark first synthesized and then isolated heronapyrrol D (42) (Figure 10) from the same marine-derived microbe [36]. Heronapyrrol D displays bioactivity against Gram-positive bacteria Staphylococcus aureus ATCC 25923 (IC50 = 1.8 μM), Staphylococcus epidermidis ATCC 12228 (IC50 = 0.9 μM), and Bacillus subtilis ATCC 6633 (IC50 = 1.8 μM). However, it is inactive against the Gram-negative bacteria Pseudomonas aeruginosa ATCC 10145 and Escherichia coli ATCC 25922.
To determine the relative and absolute stereochemistry of (+)-41, Stark and coworkers proposed and synthesized the most likely stereostructure of its enantiomer (−)-41, based on a biomimetic polyepoxide cyclization [37]. The same authors also reported the preparation of a bioisosteric carboxylate analog of (−)-41 [38].
The first total synthesis of (+)-41 was reported in 2014 by Brimble and coworkers, who used as key steps to introduce the five stereogenic centers a Julia–Kocienski coupling, a Shi epoxidation, and a catalytic epoxide-opening reaction [39]. The same year, the first total synthesis of (+)-42 was achieved by Capon and Stark using a similar approach [36]. In 2016, Brimble and Furkert reviewed the isolation and synthesis of this family of compounds [40].
Later on, the same authors reported another total synthesis for both (+)-41 and (+)-42 [41]. Shi epoxidation of diol 43, followed by CSA-catalyzed epoxide opening and cyclization, produces diastereomerically pure 44 in 75% yield over two steps. A further eight steps, with 31% yield over them, produces intermediate 45, which deprotection gives (+)-heronapyrrol D (42). Epoxidation of 42 with a Shi ketone catalyst, followed by CSA-catalyzed epoxide opening, produced enantiomerically pure (+)-heronapyrrol C (41) in 75% yield (Scheme 4).
Other synthetic approaches towards the 2-nitropyrrole system have been investigated by Brimble and Furkert, finding that Sonogashira coupling of 4-iodo-2-nitropyrrole with the appropriate alkyne was more effective than an approach relying on Stille coupling [42].

3.2.2. Kumausallene and Kumausyne

(−)-Kumausallene (46) was isolated in 1983 from the marine red alga Laurencia nipponica Yamada [43]. This compound belongs to a family of non-isoprenoid sesquiterpenes that contain a 2,6-dioxa-bicyclo [3.3.0]octane core with an exo-cyclic bromoallene (Figure 11).
In 1993, the first total synthesis of (±)-46 was reported by Overman, who chose a hexahydrobenzofuranone 47 (obtained by a Prins cyclization–pinacol rearrangement from 48) as the key intermediate for the construction of the bis-tetrahydrofuran unit (Scheme 5). Further transformation of 47 into bicyclic lactone 49 (within three further steps) and final methanolisis and tandem cyclization of the corresponding hydroxyester provided, in good yield, the desired dioxabicyclo [3.3.0]octane 50 [44].
In 2011, a synthetic approach for (−)-46 by Tang employed a desymmetrization strategy for the formation of the 2,5-cis-substituted THF ring [45]. C2-symmetric diol 51 is desymmetrized by a palladium-catalyzed cascade reaction to form lactone 52 in 87% yield (Scheme 6). The total synthesis comprised just 12 steps from commercial acetylacetone. In 2015, Ramana et al. published a different formal total synthesis of (−)-46 based on a chiral pool approach [46].
(+)-Trans-Kumausyne (53) (Figure 12) is a halogenated non-isoprenoid sesquiterpene isolated in 1983 from red alga Laurencia nipponica Yamada [47]. Its first total synthesis was achieved in 1991 by Overman and coworkers [48]. A review covering the synthetic approaches towards kumausallene and kumausyne, and other natural products containing a 2,3,5-trisubstituted tetrahydrofuran moiety, was published by Fernandes in 2020 [18].

3.3. Diterpenes

3.3.1. Darwinolide

(+)-Darwinolide (54) (Figure 13) is a diterpene isolated in 2016 by Baker from the Antarctic Dendroceratid sponge Dendrilla membranosa [49]. It presents fourfold selectivity against a biofilm phase of methicillin-resistant Staphylococcus aureus (IC50 of 33.2μM), compared to the planktonic phase (with the higher MIC of 132.9 μM). This interesting property and its low mammalian cytotoxicity (IC50 of 73.4 mM) against a J774 macrophage cell line turn darwinolide into a possible scaffold for antibiofilm-specific antibiotics. Additionally, it was found to have modest activity (11.2 μM) against L. donovani-infected macrophages [50].
Its total synthesis was reported in 2019 by Christmann [51]. The required tetrahydrofuranyl ring is installed starting from the commercially available anhydride 55, which is converted to the 2,5-dimethoxylated tetrahydrofuran 56 in four steps. A sequence of oxidation (with o-iodoxybenzoic acid), saponification, and Criegee oxidation with Pb(OAc)4 is then used to convert 56 into 57 in 61% yield over three steps (Scheme 7). A further 14 linear steps are needed to complete the total synthesis of 54, with an overall yield of 1.4%.

3.3.2. Uprolides

Cembranolides are a family of compounds related to cembrene, which is a 14-membered macrocyclic diterpene with multiple (E)-double bonds. Among them, uprolides are a subfamily of compounds named after the University of Puerto Rico. Uprolides A–G were isolated in 1995 by Rodríguez and coworkers from the Caribbean gorgonian Eunicea Mammosa and their structure was assigned by spectroscopic methods and chemical interconversion [52,53]. They are the first natural cembranolides from a Caribbean gorgonian that bear a double bond at C6 or C8. While uprolides A–C show an epoxy moiety, uprolides D–G seemed to contain a tetrahydrofuran moiety instead. Uprolides D (58), D acetate (59), D diacetate (60), and E acetate (61) (Figure 14) present a moderate cytotoxicity against HeLa cells ((IC50 = 2.5 to 5.1 µg/ ml). Moreover, 59 shows cytotoxicity against the following human tumor cell lines: CCRF-CEM T-cell leukemia (IC50 = 7.0 μg/mL), HCT-116 colon cancer (IC50 = 7.0 μg/mL), and MCF-7 breast adenocarcinoma (IC50 = 0.6 μg/mL).
Later structural revisions determined the presence of a tetrahydropyran ring, instead of the previously proposed tetrahydrofuran, in uprolides F diacetate and G acetate, hypotheses that were confirmed by asymmetric total synthesis of these natural products [54,55,56,57].
In 2007, a synthetic approach to obtain the macrocyclic core of 58 was proposed by Ramana [58]. The formation of the macrocyclic core is produced by ring-closing metathesis (RCAM) using a Grubbs’ first-generation catalyst. The RCAM of acetate 62 produces 13-membered macrocyclic 63 in 67% yield (Scheme 8). The macrocyclic core of uprolide E could not be synthesized using the same methodology.
Marshall developed a synthetic route for C1/C14 bis-epimer of 58 in which the macrocyclization is produced by an intramolecuar Barbier reaction [59]. Some years later, other members of the uprolide family, which lack the tetrahydrofuran ring, have been isolated from the gorgonian octocoral Eunicea succinea [60].

3.4. Triterpenes

3.4.1. Intricatetraol

Intricatetraol (64) is a halogenated triterpenoid with a C2 symmetry that was isolated in 1993 from the red alga Laurencia intricata (Figure 15). Suzuki and coworkers observed that a crude fraction of the extract showed cytotoxic activity against P388 leukemia cells with an IC50 value of 12.5 μg/mL. Nevertheless, pure intricatetraol was no longer active after chromatography. At first, its stereostructure was proposed as being based on its hypothetical biogenesis [61]. In 2006, Morimoto confirmed this assignment by synthesizing a degradation product of intricatetraol through a two-directional synthesis [62].
One year later, Morimoto completed the asymmetric total synthesis of (+)-64 and, thus, determined its absolute configuration [63]. The tetrahydrofuran ring 65 was stereospecifically constructed by treatment of diepoxyalcohol 66 with lithium hydroxide aqueous solution. A further 10 steps (with an accumulated yield of 30%) were needed to obtain intermediate 67, which was then dimerized to afford 68 by olefin metathesis with a second-generation Grubbs catalyst. Final diimide reduction of intermediate 68 produced (+)-64 (Scheme 9).

3.4.2. Omaezakianol

Omaezakianol (69) (Figure 16) is a squalene-derived triterpene polyether that was isolated in 2008 from the red alga Laurencia omaezakiana by Morimoto and coworkers [64]. The same group rapidly reported its first asymmetric total synthesis and, therefore, stablished its absolute configuration [65]. Key steps were olefin cross-metathesis and an epoxide-opening cascade.
In 2010, Corey reported a short total synthesis via a biomimetic epoxide-initiated cationic cascade reaction [66]. Compound 70 was treated with camphorsulfonic acid (CSA) to induce the epoxide-opening cascade cyclization, producing 71. Reduction of 71, with sodium in acetone under reflux, formed the terminal double bond with opening of the THF ring, affording 69 in 76% yield (Scheme 10). Thus, the synthesis was accomplished in just six steps from squalene.
Another biomimetic epoxide-opening cascade for the synthesis of (+)-69 was reported in 2013 by Morimoto and coworkers [67]. The cascade, which mimics the direct hydrolysis mechanism of epoxide hydrolases, begins with 5-exo cyclization of the terminal epoxide triggered by Brønsted acid catalysis. Intermediate 72 then undergoes an epoxide-opening cascade reaction with TfOH to afford (+)-69 in 33% yield (Scheme 11).

3.4.3. Longilenes

Longilenes are triterpene polyethers that were first isolated from the wood of Eurycoma longifolia in the form of (−)-longilene peroxide ((−)-73) [68,69]. In 2001, Morimoto accomplished its total synthesis [70] and determined its absolute configuration. The same author also developed a biomimetic synthesis of the C9–C16 fragment of oxasqualenoids in an enantioselective manner [71]. This chiral building block could be used as an advanced intermediate for the synthesis of different polyethers, such as teurilene, longilene peroxide, or glabrescol.
In 2018, Fernández and Daranas reported the isolation of other members of the family, namely (+)-longilene peroxide ((+)-73), longilene (74), and the derivative (+)-prelongilene ((+)-75), from the red seaweed Laurencia viridis [72]. These compounds present Ser/Thr protein phosphatase 2A inhibitory activity (Figure 17). To date, no synthetic approaches have been reported.

3.4.4. Laurokanols and Yucatecone

In 2021, laurokanols A–E (76–80) and yucatecone (81) (Figure 18), polyether triterpenes, were isolated from the red alga Laurencia viridis [73]. Laurokanols have an unprecedented tricyclic core with an [6,6]-spiroketal system. Yucatecone is the first compound of this series with an R configuration at the C14 position. A biogenetic model, supported by DFT calculations, was then postulated for the biogenesis of yucatecone.

3.4.5. Thyrsenol

Thyrsenol A (82) and B (83) (Figure 19) are polyether squalene derivatives that were isolated by Norte and coworkers in 1997 from the red alga Laurencia viridis [74]. Although both compounds show high activity against murine lymphoid neoplasm P-388 cells, compound 83 induced significantly higher inhibitory effects [75]. Other related compounds, such as thyrsiferol derivatives and dehydrovenustatriol, were found to be even more active. Therefore, it was postulated that the presence of a flexible chain around C14 to C19, and its configuration, are of particular importance for the bioactivity of these compounds. Later, Fernández and coworkers also found 83 to have protein phosphatase PP2A inhibitory activity [76]. The activity was comparable to that of dehydrothyrsiferol and thysiferyl-23-acetate, concluding that a hydroxyl group at C15 or C16 is a key factor for their intrinsic activity. In 2011, the isolation of other derivatives has been reported [77].

3.4.6. Saiyacenol

Saiyacenols A (84) and B (85) (Figure 20) are triterpene polyethers that were isolated in 2012 from the red alga Laurencia viridis. Both inhibit cell proliferation of various human tumor cell lines (MM144 (human multiple myeloma), HeLa (human cervical carcinoma), CADO-ES1 (human Ewing’s sarcoma), and show the best inhibitory activity against Jurkat (human T-cell acute leukemia) [78]. In 2015, saiyacenol C (86), and two hydroxylated derivatives 87 and 88, were isolated from the same alga [79]. Although saiyacenols showed no activity toward a range of bacteria and fungal strains, compounds 85 and 86 avoid Navicula cf. salinicola and Cylindrotheca sp. growth, while compounds 87 and 88 were also active against germination of Gayralia oxysperma.
More recently, Piñero and Fernández evaluated a range of natural and semisynthetic terpenoid polyethers against protozoan parasites of the Trypanosoma and Leishmania genera [80]. Both 84 and 85 have anti-protozoal activity against Leishmania amazonensis (IC50 = 12.96 and 10.32 μM, respectively). Interestingly, saiyacenol A 84 was also effective against the highly resistant Trypanosoma cruzi (IC50 = 13.75 ± 2.28 μM). The semisynthetic 28-iodosaiyacenol B showed a high value (IC50 = 5.40 ± 0.13 μM) against Leishmania amazonensis and no toxicity to murine macrophage J774.A1. This turns it into a possible scaffold for antikinetoplastid drugs, as the data are comparable to those of the reference drug miltefosine (IC50 = 6.48).
Very recently, Nishikawa and Morimoto reported the asymmetric total synthesis of saiyacenol A, along with that of the related Aplysiol B [81]. In their research, an epoxide-opening cascade was used to form both THF rings in the same step (Scheme 12). Thus, from advanced precursor 89, treatment with CSA provoked two sequential 5-exo openings to form the oxygenated rings in bis-tetrahydrofuran 90. The last step consisted of cross-methathesis with the ruthenium catalyst 91 and later bromoetherification with BDSB. Preliminary cytotoxicity was tested against P388, HT-29, and HeLa tumor cell lines, showing values of 5.4, 85, and >100 μM, respectively.

3.4.7. Teurilene

Teurilene (92) (Figure 21) is a triterpene polyether that was isolated in 1985 from the red alga Laurencia obtusa by Kurosawa and coworkers [82]. It has three linked 2,5-disubstituted THF rings and, even though it has eight stereogenic centres, it is an achiral compound due to its meso-symmetry (Cs). Compound 92 has a remarkable cytotoxic activity against KB cells (IC50 = 7.0 μg mL−1) [69]. Synthetic approaches and routes up to 2014 are commented on in a previous review [83].

3.4.8. Thyrsiferol

Thyrsiferol (93) is a polyoxygenated triterpenoid ether that was isolated in 1978 from the red alga Laurencia thyrsifera [84]. Its absolute stereochemistry (Figure 22) was determined in 1986 when venustatriol was isolated, since the latter could be crystallized and characterized by X-ray diffraction [85]. During the next two decades, a plethora of thyrsiferol derivatives have been isolated. Their biological profiles (cytotoxic, anti-viral, anti-tumor) have attracted much attention and several syntheses were published and reviewed in 2008 [86].
Thyrsiferol has later been found to inhibit hypoxia-induced hypoxia-inducible factor-1 (HIF-1) activation in T47D human breast tumor cells, as well as to inhibit a mitochondrial ETC complex I and show tumor cell line-selective time-dependent inhibition of cell viability/proliferation [77]. In addition, Piñero and Fernández recently reported it to be active against Acanthamoeba castellanii trophozoites (IC50 = 13.97 μM). Its derivative, 22-hydroxydehydrotyrsiferol, was similarly active (IC50 = 17.00 μM) and both were not toxic against murine macrophages, which makes them potential leads for the discovery of novel amoebicidal substances [87].

3.4.9. Rhabdastins

The first members of this family, Rhabdastins A-G, were first isolated in 2010 by Iwagawa from the sponge Rhabdastrella globostellata [88]. They belong to the group ofisomalabaricane triterpenes. In 2021, the tetrahydrofuran-containing rhabdastins H (94) and I (95) (Figure 23) were isolated from the sponge Rhabdastrella sp. [89]. They are the first marine isomalabaricanes that present a tetrahydrofuran unit in their structure. Both compounds show antiproliferative effect against K562 (IC50 11.7 and 9.8 μM, respectively) and Molt4 (IC50 16.5 and 11.0 μM) leukemic cells.

3.5. Meroterpenes

3.5.1. Alisiaquinones and Alisiaquinol

Alisiaquinones A–C (96–98) and alisiaquinol (99) (Figure 24) are meroterpenes that were isolated in 2008 from a New Caledonian deep-water sponge [90]. They display mild antimalarial activity, but the high level of toxicity (100% and 80% mortality, respectively) shown in in vivo assays limited their interest as antimalarial agents. Nevertheless, their structure can be an inspiration for the development of related structures towards novel antimalarial drugs.

3.5.2. Tricycloalterfurenes

Tricycloalterfurenes A–D (100–103) were isolated in 2017 from the culture extract of an Alternaria alternata strain (k21-1) isolated from the surface of the marine red alga Lomentaria hakodatensis [91]. These meroterpenes present activity against three phytoplankton (Chattonella marina, Heterosigma akashiwo, and Prorocentrum donghaiense) and one marine zooplankton (Artemia salina). The higher activity of tricycloalterfurene A (64, 37, 46%, respectively, against the phytoplankton species) indicates that hydroxylation at C2 or C3 negatively influences the activity against these organisms. Later, Oh and Shin reported the isolation, from a marine-derived Stemphylium sp. fungus, of tricycloalterfurenes E–G (104–106) [92]. Very recently, Fraga proposed some structural revisions [93]. Regarding tricycloalterfurenes A–C, the correct configuration of the hydroxyl group would be 4R (Figure 25), comparing the NMR data with that of guignardone T [94]. With respect to trycicloalterfurene D, the correct configuration was proposed to be 6-β-OH (6R), also by NMR data comparison to similar systems [95]. To date, no synthetic approaches have been reported.

3.5.3. Marinoterpins

Marinoterpins A–C (107–109) (Figure 26) are linear merosesterterpenoids that were recently isolated (2021) by Winter and Fenical from the marine-derived actinomycete bacteria Streptomyces sp. AJS-327 and CNQ-253 [96]. Due to their similarity to the aurachin family of compounds, a marinoterpin biosynthetic cluster (mrt) was identified. Thus, a biosynthetic route for the 3-geranylfarnesyl-2-methylquinoline core was proposed, although the reactions that lead to the tetrahydrofuran rings as well as the N-oxidation still remain unknown.

4. Other Tetrahydrofuran Derivatives

4.1. Substituted Tetrahydrofurans

4.1.1. Pachastrissamine (Jaspine B)

Pachastrissamine (110) was first isolated by Higa and coworkers from a marine sponge of the genus Pachastrissa [97]. A year later, Debitus reported its isolation from another sponge Jaspis sp. and, thus, named the compound jaspine B [98]. Other related compounds were also isolated, including jaspine A (111) (Figure 27). Pachastrissamine is a sphingolipid—in particular, a derivative from anhydrophytosphingosine. Its biological activity and synthetic endeavors until 2016 were summarized by Martinková in a mini-review [99].

4.1.2. Myrothecols

In 2020, (−)-1S-myrothecol ((−)-112), (+)-1R-myrothecol ((+)-112), and methoxy-myrothecol (113) (Figure 28) were isolated from deep-sea fungus Myrothecium sp. BZO-L062 [100]. Enantiomers (−)-112 and (+)-112 were separated by normal-phase chiral HPLC, and their absolute configurations were established by ECD spectra. Compounds (−)-112 and (+)-112 display anti-inflammatory activity, inhibit nitric oxide formation in lipopolysaccharide-treated cells (RAW264.7), and present antioxidant activity in the 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and oxygen-radical absorbance capacity assays.

4.1.3. Astronypyrone, Astronyquinone, and Astronyurea

In 2016, astronypyrone (114), astronyquinone (115), and astronyurea (116) (Figure 29) were isolated from the marine fungus Astrosphaeriella nypae BCC 5335 [101]. Compound 115 shows weak antituberculosis activity (with a MIC value of 50 μg/mL) and presents cytotoxicity against African green monkey kidney fibroblast cell lines (IC50 = 17.4 μg/mL).

4.1.4. Sinularones

Sinularones A-I were isolated in 2012 from the marine soft coral Sinularia sp. [102]. Their structures were elucidated by IR, MS, CD, 1D, and 2D NMR. Among them, sinularones E (117) and F (118) contain a tetrahydrofuran moiety (Figure 30).
Their first total synthesis, based on a hydrogenative metathesis of enynes, was reported in 2020 by Fürstner and coworkers [103]. The required 2,5-cis-tetrahydrofuran derivative 119 was readily obtained by hydrogenation (over Rh/Al2O3) of commercial furane 120. Three further steps were needed to obtain silyl ether 121, which in the presence of ruthenium catalyst 122 and H2 undergoes a hydrogenative metathesis. Later deprotection with TBAF produces 117 with 65% yield over both steps. Sinularone F (118) synthesis utilizes the same strategy (Scheme 13).

4.1.5. (+)-Varitriol

(+)-Varitriol ((+)-123) (Figure 31) was isolated in 2002 from a marine-derived strain of the fungus Emericella variecolor [104]. Its structure and relative stereochemistry were determined by NMR studies. It displays low cytotoxic activity against leukemia, ovarian, and colon cells, but its response to renal, CNS, and breast cancer cell lines was very promising (of the range of GI50 = 1.63–2.44·10−7 M). In 2006, Jennings and coworkers achieved the first total synthesis of its enantiomer (-)-123 and, thus, determined its absolute stereochemistry [105].
Its activity towards the mentioned cancer cell lines attracted the attention of synthetic chemists; different synthetic approaches for (+)-123 appeared in the next few years [106]. Taylor employed a known tetrahydrofuran-2,3,4-triol derivative as the starting material for the synthesis (in three further steps) of the desired (−)-123 and its 3′-epi-derivative [107]. Srihari also achieved the synthesis of (−)-123, (+)-123, and its 6′-epi-derivative starting from commercial D-(−)-ribose [108,109]. Krause performed a modular synthesis of (+)-123 in 10 steps, with an overall yield of 6,4% [110]. The key tetrahydrofuran with the appropriate four stereocenters 124 was prepared in four linear steps from a known enyne. Thus, Sharpless epoxidation and benzylation of (E)-hex-2-en-4-yn-1-ol provided propargyl epoxide 125 in 47% yield over two steps. A copper hydride-catalyzed reduction of 125, followed by a gold-catalyzed cycloisomerization, furnished the key dihydrofuranyl intermediate 126, with two of the required stereogenic centers. Final Sharpless dihydroxylation of 126 afforded 124 as a satisfactory 78:22 mixture of diastereoisomers. The desired natural product was obtained in a further four steps (Scheme 14).
A recent example of the total synthesis of (+)-123 was reported by Cordero-Vargas [111]. In this approach, the tetrahydrofuranyl key intermediate 127, bearing the four precise sterocenters, was obtained from commercial L-ribono-1,4-lactone in six steps. The key step in this process is the stereocontrolled nucleophilic addition to five-membered oxocarbenium ions directed by the protecting groups. Thus, TBS-protected lactone 128, obtained in four conventional steps from L-ribono-1,4-lactone, undergoes acetylide addition; a subsequent Lewis acid promoted oxocarbenium ion formation. The following stereoselective hydride attack provides tetrahydrofuran 127 as a single diastereomer in 60% yield. The final synthesis of (+)-123 is achieved in a further four steps with 31% yield over them (Scheme 15).
Later on, Qin developed a direct cross-coupling between terminal alkynes and glycosyl acetates, which was applied to the formal synthesis of (+)-123 and analogues [112]. More recently, Wang and coworkers reported another formal synthesis of (+)-123 [113]. They developed a chromium-catalyzed enantioconvergent allenylation of aldehydes to synthesize α-allenols from racemic propargyl halides. Starting from silylated propargyl bromide 129 and benzyloxyacetaldehyde, allenol 130 can be accessed through the developed procedure. The chromium catalyst was formed in situ by the addition of chromium chloride and the oxazoline ligand (R,S)-131. Manganese acted as a reducing agent, and Cp2ZrCl2 as a dissociation reagent. Then, removal of the silyl group with tetrabutylammonium fluoride gave advanced intermediate 132 in 82% yield, thus accomplishing the formal synthesis of the desired (+)-123 (Scheme 16).

5. Conclusions

Terpenes and related compounds represent an important family of marine-derived metabolites. The great number of studies focused on their biological activities and total synthesis remark their importance. We have summarized the most active compounds for a variety of bioactivities (see Table 2). Trans-oxylipid has shown nematocidal properties against Haemonchus contortus (LD50 = 1.8 ppm) and Trichostrongyllus colubriformis (LD50 = 9.9 ppm). These values, comparable to the commercial levamisole and closantel, make this compound an interesting scaffold for the development of antihelmintic substances. Though not related to drug development, we want to remark the biological interest of (+)-PMA. Its potent olfactory response in sea lampreys makes it very valuable for the control and conservation of lamprey populations. Efforts should be made in developing a total synthesis for this compound, as none has been reported to date. Mutafuran D has antifungal activity, showing a moderate value of MIC = 4 mg/mL against Cryptococcus neoformans var. grubii. Although not an impressive value, further studies could shed light on the structure–activity relationship of this brominated ene-yne tetrahydrofuran derivative. Furoplocamioid C could serve as a lead for novel biopesticides, as it has shown a potent antifeedant effect against Leptinotarsa decemlineata, with an EC50 of 19.1 nmol/cm2, Myzus Persicae (EC50 of 3.7 nmol/cm2), and Ropalosiphum Padi (EC50 of 1.6 nmol/cm2) but it has low mammalian toxicity and phytotoxic effects. With respect to antibacterial activity, heranopyrrole D has shown very good values against Staphylococcus aureus ATCC 25923 (IC50 = 1.8 mM), Staphylococcus epidermidis ATCC 12228 (IC50 = 0.9 mM), and Bacillus subtilis ATCC 6633 (IC50 = 1.8 mM); thus, the nitropyrrole moiety should be further studied to determine whether it plays an important role in its antibacterial behavior. On the other hand, though (+)-darwinolide shows a more moderate value against Staphylococcus aureus (IC50 = 33.2 μM), its selectivity towards the biofilm phase and its low toxicity makes it a very good lead for the development of antibiofilm-specific antibiotics.
Regarding antitumoral applications, there are several compounds that have shown very promising activities. Uprolide D acetate has cytotoxic activity against different tumor cell lines: HeLa cells (IC50 = 2.5 mM), CCRF-CEM T-cell leukemia (IC50 = 7.0 mM), HCT-116 colon cancer (IC50 = 7.0 mM), and MCF-7 breast adenocarcinoma (IC50 = 0.6 mM). Thyrsenol B has an impressive potential against murine lymphoid neoplasm P-388 cells (IC50 = 0.016 mM). Saiyacenol B shows antiproliferative activity against tumor cell lines MM144 human multiple myeloma (IC50 = 11.0 mM), HeLa human cervical carcinoma (IC50 = 24.5 mM), CADO-ES1 human Ewing’s sarcoma (IC50 = 14.0 mM), and possesses a very good value for Jurkat (human T-cell acute leukemia): IC50 = 2.7 mM. Furthermore, it presents antifouling activity against Navicula cf. salinicola (IC50 = 17.2 mM) and Cylindrotheca sp. (IC50 = 17.0 mM). Finally, (+)-varitriol is a very interesting example, as it is quite a simple molecule with powerful properties. It presents submicromolar activities against different cancer cell lines, namely RXF-393 (Renal cancer cell) GI50 = 0.16 μM; SNB-75 (CNS cancer cell) GI50 = 0.24 μM; and DU-145 (breast cancer cell) GI50 = 0.11 μM. Although some efforts have already been made and different total syntheses reported, we believe that further studies should point to the synthesis of analogs and the study of structure–activity relationships in this simple scaffold.
Regarding antiprotozoal activity, saiyacenol B shows a good IC50 of 10.3 mM against Leishmania amazonensis. Interestingly it was surpassed by its synthetic counterpart, 28-iodo-saiyacenol B, with a value of IC50 = 5.4 mM pointing to an interesting effect of this 28-iodo-substitution. Alisiaquinone C presents antimalarial activity in vitro against the chloroquine-resistant strains MC29 CQR (IC50 = 0.08 mM) and B1 CQR (IC50 = 0.21 mM), and the chloroquine-sensitive strain F32 CQS (IC50 = 0.15 mM). Though it presents a high toxicity, similar structures that preserve antimalarial activity and have reduced toxicity values could be developed. A possible lead for anti-inflammatory development is myrothecol: it shows antioxidant activity with an EC50 = 1.2 mg/mL (S isomer) and EC50 = 1.4 mg/mL (R isomer), inhibits nitric oxide formation, and displays anti-inflammatory activity. It is also a small molecule and, thus, its synthesis will require lower effort.
In conclusion, the tetrahydrofuran moiety is a common motif found in a variety of such compounds, which has meant a particular emphasis of researchers on the development of new methodologies for the synthesis of such derivatives. In this context, total synthesis is a powerful tool to have access to these natural products. Firstly, it is an invaluable means for the determination of the structure and total configuration of natural compounds since, in some cases, the available NMR methods are insufficient in definitively determining the structures of biologically relevant substances. Secondly, since extracting and purifying compounds from natural sources are difficult and time-consuming processes, total synthesis has emerged as a suitable solution for the production of larger amounts of compounds, thus bringing possibilities for further biological studies, the discovery of novel drug candidates, and the expansion of the medicinal chemistry frontiers.

Author Contributions

Writing—original draft preparation, L.F.-P. and P.G.-A.; writing—reviewing and editing, C.D.-P. and A.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the “Junta de Castilla y León”, grant number VA294-P18.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Acknowledgments

L.F.-P. and P.G.-A. acknowledge predoctoral grants funded by the “Junta de Castilla y León” and the University of Valladolid, respectively.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

Ac: acetate; Aq.: aqueous; BDSB: bromodiethylsulfonium bromopentachloroantimonate; Bn: benzyl; Boc: tert-butyloxy carbonyl; Bu: butyl; Bz: benzoyl; Cat.: catalyst; CD: circular dichroism; Cp: cyclopentadienyl; CSA: camphorsulfonic acid; Cy: cyclohexyl; D-(−)-DET: (−)-diethyl D-tartrate; DDQ: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone; DFT: density functional theory; (DHQD)2PYR: hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether; DIAD: diisopropyl azodicarboxylate; DME: dimethoxyethane; DMSO: dimethylsulfoxide; dr: diastereomeric ratio; ECD: electronic circular dichroism; ee: enantiomeric excess; HMDS: hexamethyl disilazide; HPLC: high-performance liquid chromatography; IBX: orto-iodoxybenzoic acid; IR: infrared; M: molar; MS: mass spectrometry; Ms: methanesulfonyl; NMR: nuclear magnetic resonance; PAB: para-aminobenzoate; PG: protecting group; Ph: phenyl; PMA: petromyric acid A; PMB: petromyric acid B or para-methoxybenzyl; PNB: para-nitrobenzoate; p-NBA: para-nitrobenzoic acid; Pr: propyl; TBAF: tetrabutylammonium fluoride; TBHP: tert-butyl hydroperoxide; TIPS: triisopropylsilyl; TfOH: trifluoromethanesulfonic acid; TMS: trimethylsilyl.

References

  1. Jiménez, C. Marine Natural Products in Medicinal Chemistry. ACS Med. Chem. Lett. 2018, 9, 959–961. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine Natural Products. Nat. Prod. Rep. 2021, 38, 362–413. [Google Scholar] [CrossRef]
  3. Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine Natural Products. Nat. Prod. Rep. 2020, 37, 175–223. [Google Scholar] [CrossRef] [PubMed]
  4. Carroll, A.R.; Copp, B.R.; Davis, R.A.; Keyzers, R.A.; Prinsep, M.R. Marine Natural Products. Nat. Prod. Rep. 2019, 36, 122–173. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Fuwa, H. Structure determination, correction, and disproof of marine macrolide natural products by chemical synthesis. Org. Chem. Front. 2021, 8, 3990–4023. [Google Scholar] [CrossRef]
  6. Caso, A.; da Silva, F.B.; Esposito, G.; Teta, R.; Sala, G.D.; Cavalcanti, L.P.A.N.; Valverde, A.L.; Martins, R.C.C.; Costantino, V. Exploring Chemical Diversity of Phorbas Sponges as a Source of Novel Lead Compounds in Drug Discovery. Mar. Drugs 2021, 19, 667. [Google Scholar] [CrossRef]
  7. Ebada, S.S.; Lin, W.H.; Proksch, P. Bioactive sesterterpenes and tripterpenes from marine sponges: Ocurrence and pharmacological significance. Mar. Drugs 2010, 8, 313–346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Ebel, R. Terpenes from Marine-Derived Fungi. Mar. Drugs 2010, 8, 2340–2368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Elissawy, A.M.; El-Shazly, M.; Ebada, S.S.; Singab, A.B.; Proksch, P. Bioactive Terpenes from Marine-Derived Fungi. Mar. Drugs 2015, 13, 1966–1992. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Jiang, M.; Wu, Z.; Guo, H.; Liu, L.; Chen, S. A Review of Terpenes from Marine-Derived Fungi: 2015–2019. Mar. Drugs 2020, 18, 321. [Google Scholar] [CrossRef] [PubMed]
  11. Wu, Q.; Sun, J.; Chen, J.; Zhang, H.; Guo, Y.-W.; Wang, H. Terpenoids from Marine Soft Coral of the Genus Lemnalia: Chemistry and Biological Activities. Mar. Drugs 2018, 16, 320. [Google Scholar] [CrossRef] [Green Version]
  12. Chang, Y.-C.; Sheu, J.-H.; Wu, Y.-C.; Sung, P.-J. Terpenoids from Octocorals of the Genus Pachyclavularia. Mar. Drugs 2017, 15, 382. [Google Scholar] [CrossRef] [Green Version]
  13. Avila, C. Terpenoids in Marine Heterobranch Molluscs. Mar. Drugs 2020, 18, 162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Hegazy, M.E.F.; Mohamed, T.A.; Alhammady, M.A.; Shaheen, A.M.; Reda, E.H.; Elshamy, A.I.; Aziz, M.; Paré, P.W. Molecular Architecture and Biomedical Leads of Terpenes from Red Sea Marine Invertebrates. Mar. Drugs 2015, 13, 3154–3181. [Google Scholar] [CrossRef] [PubMed]
  15. Nasir, N.M.; Ermanis, K.; Clarke, P.A. Strategies for the construction of tetrahydropyran rings in the synthesis of natural products. Org. Biomol. Chem. 2014, 12, 3323–3335. [Google Scholar] [CrossRef] [PubMed]
  16. Fuwa, H. Contemporary Strategies for the Synthesis of Tetrahydropyran Derivatives: Application to Total Synthesis of Neopeltolide, a Marine Macrolide Natural Product. Mar. Drugs 2016, 14, 65. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Barbero, H.; Díez-Poza, C.; Barbero, A. The Oxepane Motif in Marine Drugs. Mar. Drugs 2017, 15, 361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Fernandes, R.A.; Pathare, R.S.; Gorve, D.A. Advances in Total Synthesis of Some 2,3,5-Trisubstituted Tetrahydrofuran Natural Products. Chem. Asian J. 2020, 15, 2815–2837. [Google Scholar] [CrossRef]
  19. Fernandes, R.A.; Gorve, D.A.; Pathare, R.S. Emergence of 2,3,5-trisubstituted tetrahydrofuran natural products and their synthesis. Org. Biomol. Chem. 2020, 18, 7002–7025. [Google Scholar] [CrossRef] [PubMed]
  20. Fernández-Peña, L.; Díez-Poza, C.; González-Andrés, P.; Barbero, A. The Tetrahydrofuran Motif in Polyketide Marine Drugs. Mar. Drugs 2022, 20, 120. [Google Scholar] [CrossRef]
  21. Warren, R.G.; Wells, R.J.; Blount, J.F. A novel lipid from the brown alga Notheia anomala. Aust. J. Chem. 1980, 33, 891–898. [Google Scholar] [CrossRef]
  22. Capon, R.J.; Barrow, R.A.; Rochfort, S.; Jobling, M.; Skene, C.; Lacey, E.; Gill, J.H.; Friedel, T.; Wadsworth, D. Marine nematocides: Tetrahydrofurans from a southern Australian brown alga, Notheia anomala. Tetrahedron 1998, 54, 2227–2242. [Google Scholar] [CrossRef]
  23. Jang, H.; Shin, I.; Lee, D.; Kim, H.; Kim, D. Stereoselective Substrate-Controlled Asymmetric Syntheses of both 2,5-cis- and 2,5-trans-Tetrahydrofuranoid Oxylipids: Stereodivergent Intramolecular Amide Enolate Alkylation. Angew. Chem. Int. Ed. 2016, 55, 6497–6501. [Google Scholar] [CrossRef] [PubMed]
  24. Li, K.; Huertas, M.; Brant, C.; Chung-Davidson, Y.-W.; Bussy, U.; Hoye, T.R.; Li, W. (+)- and (−)-Petromyroxols: Antipodal Tetrahydrofurandiols from Larval Sea Lamprey (Petromyzon marinus L.) That Elicit Enantioselective Olfactory Responses. Org. Lett. 2015, 17, 286–289. [Google Scholar] [CrossRef]
  25. Mullapudi, V.; Ahmad, I.; Senapati, S.; Ramana, C.V. Total Synthesis of (+)-Petromyroxol, (−)-iso-Petromyroxol, and Possible Diastereomers. ACS Omega 2020, 5, 25334–25348. [Google Scholar] [CrossRef] [PubMed]
  26. Li, K.; Brant, C.O.; Huertas, M.; Hessler, E.J.; Mezei, G.; Scott, A.M.; Hoye, T.R.; Li, W. Fatty-acid derivative acts as a sea lamprey migratory pheromone. PNAS 2018, 115, 8603. [Google Scholar] [CrossRef] [Green Version]
  27. Morinaka, B.I.; Skepper, C.K.; Molinski, T.F. Ene-yne Tetrahydrofurans from the Sponge Xestospongia muta. Exploiting a Weak CD Effect for Assignment of Configuration. Org. Lett. 2007, 9, 1975–1978. [Google Scholar] [CrossRef] [PubMed]
  28. Zhou, X.; Lu, Y.; Lin, X.; Yang, B.; Yang, X.; Liu, Y. Brominated aliphatic hydrocarbons and sterols from the sponge Xestospongia testudinaria with their bioactivities. Chem. Phys. Lipids 2011, 164, 703–706. [Google Scholar] [CrossRef]
  29. Liu, Y.; Ding, L.; Zhang, Z.; Yan, X.; He, S. New antifungal tetrahydrofuran derivatives from a marine sponge-associated fungus Aspergillus sp. LS78. Fitoterapia 2020, 146, 104677. [Google Scholar] [CrossRef] [PubMed]
  30. Cueto, M.; Darias, J. Uncommon tetrahydrofuran monoterpenes from Antarctic Pantoneura plocamioides. Tetrahedron 1996, 52, 5899–5906. [Google Scholar] [CrossRef]
  31. Blanc, A.; Toste, F.D. Enantioselective Synthesis of Cyclic Ethers through a Vanadium-Catalyzed Resolution/Oxidative Cyclization. Angew. Chem. Int. Ed. 2006, 45, 2096–2099. [Google Scholar] [CrossRef] [PubMed]
  32. Darias, J.; Rovirosa, J.; San Martin, A.; Díaz, A.-R.; Dorta, E.; Cueto, M. Furoplocamioids A− C, Novel Polyhalogenated Furanoid Monoterpenes from Plocamium c artilagineum. J. Nat. Prod. 2001, 64, 1383–1387. [Google Scholar] [CrossRef]
  33. Díaz-Marrero, A.R.; Cueto, M.; Dorta, E.; Rovirosa, J.; San-Martín, A.; Darias, J. New halogenated monoterpenes from the red alga Plocamium cartilagineum. Tetrahedron 2002, 58, 8539–8542. [Google Scholar] [CrossRef]
  34. Argandoña, V.H.; Rovirosa, J.; San-Martín, A.; Riquelme, A.; Díaz-Marrero, A.R.; Cueto, M.; Darias, J.; Santana, O.; Guadaño, A.; González-Coloma, A. Antifeedant Effects of Marine Halogenated Monoterpenes. J. Agric. Food. Chem. 2002, 50, 7029–7033. [Google Scholar] [CrossRef] [PubMed]
  35. Raju, R.; Piggott, A.M.; Barrientos Diaz, L.X.; Khalil, Z.; Capon, R.J. Heronapyrroles A−C: Farnesylated 2-Nitropyrroles from an Australian Marine-Derived Streptomyces sp. Org. Lett. 2010, 12, 5158–5161. [Google Scholar] [CrossRef] [PubMed]
  36. Schmidt, J.; Khalil, Z.; Capon, R.J.; Stark, C.B. Heronapyrrole D: A case of co-inspiration of natural product biosynthesis, total synthesis and biodiscovery. Beilstein J. Org. Chem. 2014, 10, 1228–1232. [Google Scholar] [CrossRef] [Green Version]
  37. Schmidt, J.; Stark, C.B.W. Biomimetic Synthesis and Proposal of Relative and Absolute Stereochemistry of Heronapyrrole C. Org. Lett. 2012, 14, 4042–4045. [Google Scholar] [CrossRef]
  38. Schmidt, J.; Stark, C.B.W. Synthetic Endeavors toward 2-Nitro-4-Alkylpyrroles in the Context of the Total Synthesis of Heronapyrrole C and Preparation of a Carboxylate Natural Product Analogue. J. Org. Chem. 2014, 79, 1920–1928. [Google Scholar] [CrossRef]
  39. Ding, X.-B.; Furkert, D.P.; Capon, R.J.; Brimble, M.A. Total Synthesis of Heronapyrrole C. Org. Lett. 2014, 16, 378–381. [Google Scholar] [CrossRef]
  40. Ding, X.-B.; Brimble, M.A.; Furkert, D.P. Nitropyrrole natural products: Isolation, biosynthesis and total synthesis. Org. Biomol. Chem. 2016, 14, 5390–5401. [Google Scholar] [CrossRef]
  41. Ding, X.-B.; Furkert, D.P.; Brimble, M.A. 2-Nitropyrrole cross-coupling enables a second generation synthesis of the heronapyrrole antibiotic natural product family. Chem. Commun. 2016, 52, 12638–12641. [Google Scholar] [CrossRef]
  42. Ding, X.-B.; Brimble, M.A.; Furkert, D.P. Reactivity of 2-Nitropyrrole Systems: Development of Improved Synthetic Approaches to Nitropyrrole Natural Products. J. Org. Chem. 2018, 83, 12460–12470. [Google Scholar] [CrossRef]
  43. Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Kumausalle, a new bromoallene from the marine red alga laurencia nipponica yamada. Chem. Lett. 1983, 12, 1639–1642. [Google Scholar] [CrossRef] [Green Version]
  44. Grese, T.A.; Hutchinson, K.D.; Overman, L.E. General approach to halogenated tetrahydrofuran natural products from red algae of the genus Laurencia. Total synthesis of (.+-.)-kumausallene and (.+-.)-1-epi-kumausallene. J. Org. Chem. 1993, 58, 2468–2477. [Google Scholar] [CrossRef]
  45. Werness, J.B.; Tang, W. Stereoselective Total Synthesis of (−)-Kumausallene. Org. Lett. 2011, 13, 3664–3666. [Google Scholar] [CrossRef]
  46. Das, S.; Ramana, C.V. A formal total synthesis of (−)-kumausallene. Tetrahedron 2015, 71, 8577–8584. [Google Scholar] [CrossRef]
  47. Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Kumausynes and deacetylkumausynes, four new halogenated C-15 acetylenes from the red alga Laurencia nipponica Yamada. Chem. Lett. 1983, 12, 1643–1644. [Google Scholar] [CrossRef]
  48. Brown, M.J.; Harrison, T.; Overman, L.E. General approach to halogenated tetrahydrofuran natural products from red algae of the genus Laurencia. Total synthesis of (.+-.)-trans-kumausyne and demonstration of an asymmetric synthesis strategy. J. Am. Chem. Soc. 1991, 113, 5378–5384. [Google Scholar] [CrossRef]
  49. Von Salm, J.L.; Witowski, C.G.; Fleeman, R.M.; McClintock, J.B.; Amsler, C.D.; Shaw, L.N.; Baker, B.J. Darwinolide, a New Diterpene Scaffold That Inhibits Methicillin-Resistant Staphylococcus aureus Biofilm from the Antarctic Sponge Dendrilla membranosa. Org. Lett. 2016, 18, 2596–2599. [Google Scholar] [CrossRef]
  50. Shilling, A.J.; Witowski, C.G.; Maschek, J.A.; Azhari, A.; Vesely, B.A.; Kyle, D.E.; Amsler, C.D.; McClintock, J.B.; Baker, B.J. Spongian Diterpenoids Derived from the Antarctic Sponge Dendrilla antarctica Are Potent Inhibitors of the Leishmania Parasite. J. Nat. Prod. 2020, 83, 1553–1562. [Google Scholar] [CrossRef]
  51. Siemon, T.; Steinhauer, S.; Christmann, M. Synthesis of (+)-Darwinolide, a Biofilm-Penetrating Anti-MRSA Agent. Angew. Chem. Int. Ed. 2019, 58, 1120–1122. [Google Scholar] [CrossRef]
  52. Rodríguez, A.D.; Piña, I.C.; Soto, J.J.; Rojas, D.R.; Barnes, C.L. Isolation and structures of the uprolides. I. Thirteen new cytotoxic cembranolides from the Caribbean gorgonian Euniceamammosa. Can. J. Chem. 1995, 73, 643–654. [Google Scholar] [CrossRef]
  53. Rodríguez, A.D.; Soto, J.J.; Piña, I.C. Uprolides D-G, 2. A Rare Family of 4,7-Oxa-bridged Cembranolides from the Caribbean Gorgonian Eunicea mammosa. J. Nat. Prod. 1995, 58, 1209–1216. [Google Scholar] [CrossRef]
  54. Rodríguez, A.D.; Soto, J.J.; Barnes, C.L. Synthesis of Uprolide D− G Analogues. Revision of Structure of the Marine Cembranolides Uprolide F Diacetate and Uprolide G Acetate. J. Org. Chem. 2000, 65, 7700–7702. [Google Scholar] [CrossRef]
  55. Zhu, L.; Tong, R. Structural Revision of (+)-Uprolide F Diacetate Confirmed by Asymmetric Total Synthesis. Org. Lett. 2015, 17, 1966–1969. [Google Scholar] [CrossRef]
  56. Zhu, L.; Liu, Y.; Ma, R.; Tong, R. Total Synthesis and Structural Revision of (+)-Uprolide G Acetate. Angew. Chem. Int. Ed. 2015, 54, 627–632. [Google Scholar] [CrossRef]
  57. Zhu, L.; Tong, R. Structural Revision of Uprolide G Acetate: Effective Interplay between NMR Data Analysis and Chemical Synthesis. Synlett 2015, 26, 1643–1648. [Google Scholar] [CrossRef]
  58. Ramana, C.V.; Salian, S.R.; Gurjar, M.K. Central core of uprolides D and E: A survey of some ring closing metathesis approaches. Tetrahedron Lett. 2007, 48, 1013–1016. [Google Scholar] [CrossRef]
  59. Marshall, J.A.; Griot, C.A.; Chobanian, H.R.; Myers, W.H. Synthesis of a Lactone Diastereomer of the Cembranolide Uprolide D. Org. Lett. 2010, 12, 4328–4331. [Google Scholar] [CrossRef]
  60. Torres-Mendoza, D.; González, Y.; Gómez-Reyes, J.F.; Guzmán, H.M.; López-Perez, J.L.; Gerwick, W.H.; Fernandez, P.L.; Gutiérrez, M. Uprolides N, O and P from the Panamanian Octocoral Eunicea succinea. Molecules 2016, 21, 819. [Google Scholar] [CrossRef]
  61. Suzuki, M.; Matsuo, Y.; Takeda, S.; Suzuki, T. Intricatetraol, a halogenated triterpene alcohol from the red alga Laurencia intricata. Phytochemistry 1993, 33, 651–656. [Google Scholar] [CrossRef]
  62. Morimoto, Y.; Takaishi, M.; Adachi, N.; Okita, T.; Yata, H. Two-directional synthesis and stereochemical assignment toward a C2 symmetric oxasqualenoid (+)-intricatetraol. Org. Biomol. Chem. 2006, 4, 3220–3222. [Google Scholar] [CrossRef] [PubMed]
  63. Morimoto, Y.; Okita, T.; Takaishi, M.; Tanaka, T. Total Synthesis and Determination of the Absolute Configuration of (+)-Intricatetraol. Angew. Chem. Int. Ed. 2007, 46, 1132–1135. [Google Scholar] [CrossRef] [PubMed]
  64. Matsuo, Y.; Suzuki, M.; Masuda, M.; Iwai, T.; Morimoto, Y. Squalene-Derived Triterpene Polyethers from the Red Alga Laurencia omaezakiana. Helv. Chim. Acta 2008, 91, 1261–1266. [Google Scholar] [CrossRef]
  65. Morimoto, Y.; Okita, T.; Kambara, H. Total Synthesis and Determination of the Absolute Configuration of (+)-Omaezakianol. Angew. Chem. Int. Ed. 2009, 48, 2538–2541. [Google Scholar] [CrossRef]
  66. Xiong, Z.; Busch, R.; Corey, E.J. A Short Total Synthesis of (+)-Omaezakianol via an Epoxide-Initiated Cationic Cascade Reaction. Org. Lett. 2010, 12, 1512–1514. [Google Scholar] [CrossRef]
  67. Morimoto, Y.; Takeuchi, E.; Kambara, H.; Kodama, T.; Tachi, Y.; Nishikawa, K. Biomimetic Epoxide-Opening Cascades of Oxasqualenoids Triggered by Hydrolysis of the Terminal Epoxide. Org. Lett. 2013, 15, 2966–2969. [Google Scholar] [CrossRef]
  68. Itokawa, H.; Kishi, E.; Morita, H.; Takeya, K.; Iitaka, Y. A New Squalene-type Triterpene from the Woods of Eurycoma longifolia. Chem. Lett. 1991, 20, 2221–2222. [Google Scholar] [CrossRef]
  69. Morita, H.; Kishi, E.; Takeya, K.; Itokawa, H.; Iitaka, Y. Squalene derivatives from Eurycoma longifolia. Phytochemistry 1993, 34, 765–771. [Google Scholar] [CrossRef]
  70. Morimoto, Y.; Iwai, T.; Kinoshita, T. Total synthesis and determination of the absolute configuration of (−)-longilene peroxide. Tetrahedron Lett. 2001, 42, 6307–6309. [Google Scholar] [CrossRef]
  71. Morimoto, Y.; Iwai, T.; Nishikawa, Y.; Kinoshita, T. Stereospecific and biomimetic synthesis of CS and C2 symmetric 2,5-disubstituted tetrahydrofuran rings as central building blocks of biogenetically intriguing oxasqualenoids. Tetrahedron Asymmetry 2002, 13, 2641–2647. [Google Scholar] [CrossRef]
  72. Cen-Pacheco, F.; Pérez Manríquez, C.; Luisa Souto, M.; Norte, M.; Fernández, J.J.; Hernández Daranas, A. Marine Longilenes, Oxasqualenoids with Ser-Thr Protein Phosphatase 2A Inhibition Activity. Mar. Drugs 2018, 16, 131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Cen-Pacheco, F.; Santiago-Benítez, A.J.; Tsui, K.Y.; Tantillo, D.J.; Fernández, J.J.; Daranas, A.H. Structure and Computational Basis for Backbone Rearrangement in Marine Oxasqualenoids. J. Org. Chem. 2021, 86, 2437–2446. [Google Scholar] [CrossRef]
  74. Norte, M.; Fernández, J.; Souto, M.L.; Gavín, J.; García-Grávalos, M.D. Thyrsenols A and B, two unusual polyether squalene derivatives. Tetrahedron 1997, 53, 3173–3178. [Google Scholar] [CrossRef]
  75. Fernández, J.; Souto, M.L.; Norte, M. Evaluation of the cytotoxic activity of polyethers isolated from Laurencia. Biorg. Med. Chem. 1998, 6, 2237–2243. [Google Scholar] [CrossRef]
  76. Souto, M.A.L.; Manríquez, C.P.; Norte, M.; Leira, F.; Fernández, J.J. The inhibitory effects of squalene-derived triterpenes on protein phosphatase PP2A. Bioorg. Med. Chem. Lett. 2003, 13, 1261–1264. [Google Scholar] [CrossRef]
  77. Cen-Pacheco, F.; Villa-Pulgarin, J.A.; Mollinedo, F.; Norte, M.; Daranas, A.H.; Fernández, J.J. Cytotoxic oxasqualenoids from the red alga Laurencia viridis. Eur. J. Med. Chem. 2011, 46, 3302–3308. [Google Scholar] [CrossRef] [PubMed]
  78. Cen-Pacheco, F.; Mollinedo, F.; Villa-Pulgarín, J.A.; Norte, M.; Fernández, J.J.; Hernández Daranas, A. Saiyacenols A and B: The key to solve the controversy about the configuration of aplysiols. Tetrahedron 2012, 68, 7275–7279. [Google Scholar] [CrossRef]
  79. Cen-Pacheco, F.; Santiago-Benítez, A.J.; García, C.; Álvarez-Méndez, S.J.; Martín-Rodríguez, A.J.; Norte, M.; Martín, V.S.; Gavín, J.A.; Fernández, J.J.; Daranas, A.H. Oxasqualenoids from Laurencia viridis: Combined Spectroscopic–Computational Analysis and Antifouling Potential. J. Nat. Prod. 2015, 78, 712–721. [Google Scholar] [CrossRef] [PubMed]
  80. Díaz-Marrero, A.R.; López-Arencibia, A.; Bethencout-Estrella, C.J.; Cen-Pacheco, F.; Sifaoui, I.; Hernández Creus, A.; Duque-Ramírez, M.C.; Souto, M.L.; Hernández Daranas, A.; Lorenzo-Morales, J.; et al. Antiprotozoal activities of marine polyether triterpenoids. Bioorg. Chem. 2019, 92, 103276. [Google Scholar] [CrossRef] [PubMed]
  81. Nishikibe, K.; Nishikawa, K.; Kumagai, M.; Doe, M.; Morimoto, Y. Asymmetric Total Syntheses, Stereostructures, and Cytotoxicities of Marine Bromotriterpenoids Aplysiol B (Laurenmariannol) and Saiyacenol A. Chem. Asian J. 2022, 17, e202101137. [Google Scholar] [CrossRef] [PubMed]
  82. Suzuki, T.; Suzuki, M.; Furusaki, A.; Matsumoto, T.; Kato, A.; Imanaka, Y.; Kurosawa, E. Teurilene and thyrsiferyl 23-acetate, meso and remarkably cytotoxic compounds from the marine red alga laurencia obtusa (hudson) lamouroux. Tetrahedron Lett. 1985, 26, 1329–1332. [Google Scholar] [CrossRef]
  83. Sheikh, N.S. Synthetic endeavours towards oxasqualenoid natural products containing 2,5-disubstituted tetrahydrofurans–eurylene and teurilene. Nat. Prod. Rep. 2014, 31, 1088–1100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Blunt, J.W.; Hartshorn, M.P.; McLennan, T.J.; Munro, M.H.G.; Robinson, W.T.; Yorke, S.C. Thyrsiferol: A squalene-derived metabolite of laurencia thyrsifera. Tetrahedron Lett. 1978, 19, 69–72. [Google Scholar] [CrossRef]
  85. Sakemi, S.; Higa, T.; Jefford, C.W.; Bernardinelli, G. Venustatriol. A new, anti-viral, triterpene tetracyclic ether from Laurencia venusta. Tetrahedron Lett. 1986, 27, 4287–4290. [Google Scholar] [CrossRef]
  86. Little, R.D.; Nishiguchi, G.A. Synthetic Efforts Toward, and Biological Activity of, Thyrsiferol and Structurally-Related Analogues. In Studies in Natural Products Chemistry; Attaur, R., Ed.; Elsevier: Amsterdam, The Netherlands, 2008; Volume 35, pp. 3–56. [Google Scholar]
  87. Lorenzo-Morales, J.; Díaz-Marrero, A.R.; Cen-Pacheco, F.; Sifaoui, I.; Reyes-Batlle, M.; Souto, M.L.; Hernández Daranas, A.; Piñero, J.E.; Fernández, J.J. Evaluation of Oxasqualenoids from the Red Alga Laurencia viridis against Acanthamoeba. Mar. Drugs 2019, 17, 420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Hirashima, M.; Tsuda, K.; Hamada, T.; Okamura, H.; Furukawa, T.; Akiyama, S.-i.; Tajitsu, Y.; Ikeda, R.; Komatsu, M.; Doe, M.; et al. Cytotoxic Isomalabaricane Derivatives and a Monocyclic Triterpene Glycoside from the Sponge Rhabdastrella globostellata. J. Nat. Prod. 2010, 73, 1512–1518. [Google Scholar] [CrossRef] [PubMed]
  89. Lai, K.-H.; Huang, Z.-H.; El-Shazly, M.; Peng, B.-R.; Wei, W.-C.; Su, J.-H. Isomalabaricane Triterpenes from the Marine Sponge Rhabdastrella sp. Mar. Drugs 2021, 19, 206. [Google Scholar] [CrossRef]
  90. Desoubzdanne, D.; Marcourt, L.; Raux, R.; Chevalley, S.; Dorin, D.; Doerig, C.; Valentin, A.; Ausseil, F.; Debitus, C. Alisiaquinones and alisiaquinol, dual inhibitors of Plasmodium falciparum enzyme targets from a New Caledonian deep water sponge. J. Nat. Prod. 2008, 71, 1189–1192. [Google Scholar] [CrossRef]
  91. Shi, Z.-Z.; Miao, F.-P.; Fang, S.-T.; Liu, X.-H.; Yin, X.-L.; Ji, N.-Y. Sesteralterin and Tricycloalterfurenes A-D: Terpenes with Rarely Occurring Frameworks from the Marine-Alga-Epiphytic Fungus Alternaria alternata k21-1. J. Nat. Prod. 2017, 80, 2524–2529. [Google Scholar] [CrossRef] [PubMed]
  92. Hwang, J.-Y.; Park, S.C.; Byun, W.S.; Oh, D.-C.; Lee, S.K.; Oh, K.-B.; Shin, J. Bioactive Bianthraquinones and Meroterpenoids from a Marine-Derived Stemphylium sp. Fungus. Mar. Drugs 2020, 18, 436. [Google Scholar] [CrossRef]
  93. Fraga, B.M.; Díaz, C.E. Proposal for structural revision of several monosubstituted tricycloalternarenes. Phytochemistry 2022, 198, 113141. [Google Scholar] [CrossRef] [PubMed]
  94. Duan, X.; Tan, X.; Gu, L.; Liu, J.; Hao, X.; Tao, L.; Feng, H.; Cao, Y.; Shi, Z.; Duan, Y.; et al. New secondary metabolites with immunosuppressive activity from the phytopathogenic fungus Bipolaris maydis. Bioorg. Chem. 2020, 99, 103816. [Google Scholar] [CrossRef] [PubMed]
  95. Shi, X.; Wei, W.; Zhang, W.-J.; Hua, C.-P.; Chen, C.-J.; Ge, H.-M.; Tan, R.-X.; Jiao, R.-H. New tricycloalternarenes from fungus Alternaria sp. J. Asian Nat. Prod. Res. 2015, 17, 143–148. [Google Scholar] [CrossRef] [PubMed]
  96. Kim, M.C.; Winter, J.M.; Asolkar, R.N.; Boonlarppradab, C.; Cullum, R.; Fenical, W. Marinoterpins A–C: Rare Linear Merosesterterpenoids from Marine-Derived Actinomycete Bacteria of the Family Streptomycetaceae. J. Org. Chem. 2021, 86, 11140–11148. [Google Scholar] [CrossRef]
  97. Kuroda, I.; Musman, M.; Ohtani, I.I.; Ichiba, T.; Tanaka, J.; Gravalos, D.G.; Higa, T. Pachastrissamine, a Cytotoxic Anhydrophytosphingosine from a Marine Sponge, Pachastrissa sp. J. Nat. Prod. 2002, 65, 1505–1506. [Google Scholar] [CrossRef] [PubMed]
  98. Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G. Jaspines A and B: Two new cytotoxic sphingosine derivatives from the marine sponge Jaspis sp. Tetrahedron Lett. 2003, 44, 225–228. [Google Scholar] [CrossRef]
  99. Martinková, M.; Gonda, J. Marine cytotoxic jaspine B and its stereoisomers: Biological activity and syntheses. Carbohydr. Res. 2016, 423, 1–42. [Google Scholar] [CrossRef]
  100. Lu, X.; He, J.; Wu, Y.; Du, N.; Li, X.; Ju, J.; Hu, Z.; Umezawa, K.; Wang, L. Isolation and Characterization of New Anti-Inflammatory and Antioxidant Components from Deep Marine-Derived Fungus Myrothecium sp. Bzo-l062. Mar. Drugs 2020, 18, 597. [Google Scholar] [CrossRef]
  101. Chokpaiboon, S.; Unagul, P.; Kongthong, S.; Danwisetkanjana, K.; Pilantanapak, A.; Suetrong, S.; Bunyapaiboonsri, T. A pyrone, naphthoquinone, and cyclic urea from the marine-derived fungus Astrosphaeriella nypae BCC 5335. Tetrahedron Lett. 2016, 57, 1171–1173. [Google Scholar] [CrossRef]
  102. Shi, H.; Yu, S.; Liu, D.; Van Ofwegen, L.; Proksch, P.; Lin, W. Sinularones A–I, New Cyclopentenone and Butenolide Derivatives from a Marine Soft Coral Sinularia sp. and Their Antifouling Activity. Mar. Drugs 2012, 10, 1331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Peil, S.; Bistoni, G.; Goddard, R.; Fürstner, A. Hydrogenative Metathesis of Enynes via Piano-Stool Ruthenium Carbene Complexes Formed by Alkyne gem-Hydrogenation. J. Am. Chem. Soc. 2020, 142, 18541–18553. [Google Scholar] [CrossRef] [PubMed]
  104. Malmstrøm, J.; Christophersen, C.; Barrero, A.F.; Oltra, J.E.; Justicia, J.; Rosales, A. Bioactive Metabolites from a Marine-Derived Strain of the Fungus Emericella variecolor. J. Nat. Prod. 2002, 65, 364–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Clemens, R.T.; Jennings, M.P. An efficient total synthesis and absolute configuration determination of varitriol. Chem. Commun. 2006, 25, 2720–2721. [Google Scholar] [CrossRef]
  106. Mahesh, S.M.; Supriya, T.; Prakash, T.P. Recent Developments Towards the Synthesis of Varitriol: An Antitumour Agent from Marine Derived Fungus Emericella Variecolor. Curr. Org. Synth. 2014, 11, 268–287. [Google Scholar] [CrossRef] [Green Version]
  107. McAllister, G.D.; Robinson, J.E.; Taylor, R.J.K. The synthesis of (−)-varitriol and (−)-3′-epi-varitriol via a Ramberg–Bäcklund route. Tetrahedron 2007, 63, 12123–12130. [Google Scholar] [CrossRef]
  108. Vamshikrishna, K.; Srihari, P. A conventional approach to the total synthesis of (−)-varitriol. Tetrahedron: Asymmetry 2012, 23, 1584–1587. [Google Scholar] [CrossRef]
  109. Vamshikrishna, K.; Srihari, P. Total synthesis of (+)-varitriol and (+)-6′-epi-varitriol. Tetrahedron 2012, 68, 1540–1546. [Google Scholar] [CrossRef]
  110. Sun, T.; Deutsch, C.; Krause, N. Combined coinage metal catalysis in natural product synthesis: Total synthesis of (+)-varitriol and seven analogs. Org. Biomol. Chem. 2012, 10, 5965–5970. [Google Scholar] [CrossRef]
  111. Sánchez-Eleuterio, A.; García-Santos, W.H.; Díaz-Salazar, H.; Hernández-Rodríguez, M.; Cordero-Vargas, A. Stereocontrolled Nucleophilic Addition to Five-Membered Oxocarbenium Ions Directed by the Protecting Groups. Application to the Total Synthesis of (+)-Varitriol and of Two Diastereoisomers Thereof. J. Org. Chem. 2017, 82, 8464–8475. [Google Scholar] [CrossRef] [PubMed]
  112. He, H.; Qin, H.-B. ZnBr2-catalyzed direct C-glycosylation of glycosyl acetates with terminal alkynes. Org. Chem. Front. 2018, 5, 1962–1966. [Google Scholar] [CrossRef]
  113. Zhang, F.-H.; Guo, X.; Zeng, X.; Wang, Z. Catalytic Enantioconvergent Allenylation of Aldehydes with Propargyl Halides. Angew. Chem. Int. Ed. 2022, 61, e202117114. [Google Scholar] [CrossRef]
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Figure 1. Distribution of the number of metabolites from this review, according to their marine source (color code coincides with that of Table 1).
Figure 1. Distribution of the number of metabolites from this review, according to their marine source (color code coincides with that of Table 1).
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Figure 2. Distribution of compounds from this review according to terpenoid type.
Figure 2. Distribution of compounds from this review according to terpenoid type.
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Figure 3. Structure of trans-oxylipid 1 and cis-oxylipid 2.
Figure 3. Structure of trans-oxylipid 1 and cis-oxylipid 2.
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Scheme 1. Stereodivergent synthesis of trans- and cis-oxylipids 1 and 2 by Kim.
Scheme 1. Stereodivergent synthesis of trans- and cis-oxylipids 1 and 2 by Kim.
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Figure 4. Structures of (+)-and (-)-petromyroxol 9.
Figure 4. Structures of (+)-and (-)-petromyroxol 9.
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Scheme 2. Synthesis of (+)-petromyroxol by Ramana and coworkers.
Scheme 2. Synthesis of (+)-petromyroxol by Ramana and coworkers.
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Figure 5. Structure of (+)-PMA ((+)-17), (−)-PMA ((−)-17), (+)-PMB ((+)-18), and (−)-PMB ((−)-18).
Figure 5. Structure of (+)-PMA ((+)-17), (−)-PMA ((−)-17), (+)-PMB ((+)-18), and (−)-PMB ((−)-18).
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Figure 6. Structure of mutafurans A–G and the yne-lacking mutafuran H.
Figure 6. Structure of mutafurans A–G and the yne-lacking mutafuran H.
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Figure 7. Structure of aspericacids A 27 and B 28.
Figure 7. Structure of aspericacids A 27 and B 28.
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Figure 8. Proposed structure of pantofuranoids.
Figure 8. Proposed structure of pantofuranoids.
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Scheme 3. Vanadium-catalyzed synthesis of the tetrahydrofuranyl core of (−)-pantofuranoid E by Toste.
Scheme 3. Vanadium-catalyzed synthesis of the tetrahydrofuranyl core of (−)-pantofuranoid E by Toste.
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Figure 9. Structure of furoplocamioids A–C (38–40).
Figure 9. Structure of furoplocamioids A–C (38–40).
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Figure 10. Structure of (+)-heronapyrrol C (41) and (+)-heronapyrrol D (42).
Figure 10. Structure of (+)-heronapyrrol C (41) and (+)-heronapyrrol D (42).
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Scheme 4. Synthesis of (+)-heronapyrrol C (41) and (+)-heronapyrrol D (42).
Scheme 4. Synthesis of (+)-heronapyrrol C (41) and (+)-heronapyrrol D (42).
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Figure 11. Structure of kumausallene.
Figure 11. Structure of kumausallene.
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Scheme 5. Synthesis of the dioxabicyclo [3.3.0]octane unit of (±)-kumausallene (46) by Overman.
Scheme 5. Synthesis of the dioxabicyclo [3.3.0]octane unit of (±)-kumausallene (46) by Overman.
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Scheme 6. Synthesis of the tetrahydrofuranyl ring of (−)-46 through desymmetrization by Tang.
Scheme 6. Synthesis of the tetrahydrofuranyl ring of (−)-46 through desymmetrization by Tang.
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Figure 12. Structure of (+)-trans-Kumausyne (53).
Figure 12. Structure of (+)-trans-Kumausyne (53).
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Figure 13. Structure of (+)-darwinolide ((+)-54).
Figure 13. Structure of (+)-darwinolide ((+)-54).
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Scheme 7. Synthesis of the key THF-containing intermediate in Christmann’s total synthesis of darwinolide.
Scheme 7. Synthesis of the key THF-containing intermediate in Christmann’s total synthesis of darwinolide.
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Figure 14. Structure of tetrahydrofuran-containing members of the uprolide family.
Figure 14. Structure of tetrahydrofuran-containing members of the uprolide family.
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Scheme 8. Synthesis of macrocyclic core of uprolide D by Ramana.
Scheme 8. Synthesis of macrocyclic core of uprolide D by Ramana.
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Figure 15. Structure of (+)-intricatetraol 64.
Figure 15. Structure of (+)-intricatetraol 64.
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Scheme 9. Synthesis of (+)-intricatetraol ((+)-64).
Scheme 9. Synthesis of (+)-intricatetraol ((+)-64).
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Figure 16. Structure of (+)-omaezakianol (69).
Figure 16. Structure of (+)-omaezakianol (69).
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Scheme 10. Synthesis of (+)-omaezakianol 69 by Corey via an epoxide-initiated cationic cascade.
Scheme 10. Synthesis of (+)-omaezakianol 69 by Corey via an epoxide-initiated cationic cascade.
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Scheme 11. Synthesis of (+)-omaezakianol ((+)-69) by a biomimetic epoxide-opening cascade.
Scheme 11. Synthesis of (+)-omaezakianol ((+)-69) by a biomimetic epoxide-opening cascade.
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Figure 17. Structure of (−)-longilene peroxide ((−)-73), (+)-longilene peroxide ((+)-73), longilene (74), and the derivative (+)-prelongilene ((+)-75).
Figure 17. Structure of (−)-longilene peroxide ((−)-73), (+)-longilene peroxide ((+)-73), longilene (74), and the derivative (+)-prelongilene ((+)-75).
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Figure 18. Structures of laurokanols A–E (76–80) and yucatecone (81).
Figure 18. Structures of laurokanols A–E (76–80) and yucatecone (81).
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Figure 19. Structure of thyrsenol A (82) and B (83).
Figure 19. Structure of thyrsenol A (82) and B (83).
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Figure 20. Structure of saiyacenols A–C (84–86) and their hydroxylated derivatives 87 and 88.
Figure 20. Structure of saiyacenols A–C (84–86) and their hydroxylated derivatives 87 and 88.
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Scheme 12. Synthesis of saiyacenol A by Nishikawa and Morimoto.
Scheme 12. Synthesis of saiyacenol A by Nishikawa and Morimoto.
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Figure 21. Structure of teurilene 92.
Figure 21. Structure of teurilene 92.
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Figure 22. Structure of thyrsiferol (93).
Figure 22. Structure of thyrsiferol (93).
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Figure 23. Structure of rhabdastins H (94) and I (95).
Figure 23. Structure of rhabdastins H (94) and I (95).
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Figure 24. Structure of alisiaquinones A–C (96–98) and alisiaquinol (99).
Figure 24. Structure of alisiaquinones A–C (96–98) and alisiaquinol (99).
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Figure 25. Structure of tricycloalterfurenes and proposed structural revisions (in pink) by Fraga.
Figure 25. Structure of tricycloalterfurenes and proposed structural revisions (in pink) by Fraga.
Marinedrugs 20 00642 g025
Marinedrugs 20 00642 g026 550
Figure 26. Structure of marinoterpins A–C (107–109).
Figure 26. Structure of marinoterpins A–C (107–109).
Marinedrugs 20 00642 g026
Marinedrugs 20 00642 g027 550
Figure 27. Structures of pachastrissamine (jaspine B, 110) and jaspine A (111).
Figure 27. Structures of pachastrissamine (jaspine B, 110) and jaspine A (111).
Marinedrugs 20 00642 g027
Marinedrugs 20 00642 g028 550
Figure 28. Structure of (−)-1S-myrothecol ((−)-112), (+)-1R-myrothecol ((+)-112), and methoxy-myrothecol (113).
Figure 28. Structure of (−)-1S-myrothecol ((−)-112), (+)-1R-myrothecol ((+)-112), and methoxy-myrothecol (113).
Marinedrugs 20 00642 g028
Marinedrugs 20 00642 g029 550
Figure 29. Structure of astronypyrone (114), astronyquinone (115), and astronyurea (116).
Figure 29. Structure of astronypyrone (114), astronyquinone (115), and astronyurea (116).
Marinedrugs 20 00642 g029
Marinedrugs 20 00642 g030 550
Figure 30. Structure of sinularones E (117) and F (118).
Figure 30. Structure of sinularones E (117) and F (118).
Marinedrugs 20 00642 g030
Marinedrugs 20 00642 sch013 550
Scheme 13. Synthesis of sinularone E (117). A similar strategy was applied to sinularone F (118).
Scheme 13. Synthesis of sinularone E (117). A similar strategy was applied to sinularone F (118).
Marinedrugs 20 00642 sch013
Marinedrugs 20 00642 g031 550
Figure 31. Structure of (+)-varitriol ((+)-123) and (−)-varitriol ((−)-123).
Figure 31. Structure of (+)-varitriol ((+)-123) and (−)-varitriol ((−)-123).
Marinedrugs 20 00642 g031
Marinedrugs 20 00642 sch014 550
Scheme 14. Modular synthesis of (+)-varitriol ((+)-123) by Krause.
Scheme 14. Modular synthesis of (+)-varitriol ((+)-123) by Krause.
Marinedrugs 20 00642 sch014
Marinedrugs 20 00642 sch015 550
Scheme 15. Protecting group-directed nucleophilic addition for the synthesis of (+)-varitriol (123).
Scheme 15. Protecting group-directed nucleophilic addition for the synthesis of (+)-varitriol (123).
Marinedrugs 20 00642 sch015
Marinedrugs 20 00642 sch016 550
Scheme 16. Application of allenylation of aldehydes to the formal synthesis of (+)-varitriol by Wang.
Scheme 16. Application of allenylation of aldehydes to the formal synthesis of (+)-varitriol by Wang.
Marinedrugs 20 00642 sch016
Table
Table 1. Overview of compounds from this review, their sources, classes, and species (background color code coincides with that of Figure 1).
Table 1. Overview of compounds from this review, their sources, classes, and species (background color code coincides with that of Figure 1).
Marine SourceCompound ClassMarine SpeciesCompound Name
Lampreys
Marinedrugs 20 00642 i001		Fatty acidsPetromyzon marinus L.(+)-Petromyroxol
(−)-Petromyroxol
(+)-PMA
(−)-PMA
(+)-PMB
(−)-PMB
Corals
Marinedrugs 20 00642 i002		DiterpenesEunicea mammosaUprolides D–E
Substituted THFSinularia sp.Sinularones E–F
Algae
Marinedrugs 20 00642 i003		C19 lipid diolsNotheia anomalaTrans-oxylipid
Cis-oxylipid
MonoterpenesPlocamium cartilagineumFuroplocamioids A–C
Pantoneura plocamioidesPantofuranoids A–F
SesquiterpenesLaurencia nipponica Yamada(−)-Kumausallene
(+)-Trans-Kumausyne
TriterpenesLaurencia intricataIntricatetraol
Laurencia omaezakianaOmaezakianol
Laurencia viridisLongilenes
Laurokanols A–E
Yucatecone
Thyrsenols A–B
Saiyacenols A–C
Laurencia obtusaTeurilene
Laurencia thyrsiferaThyrsiferol
Sponges
Marinedrugs 20 00642 i004		Fatty acidsXestospongia mutaMutafurans A–G
Xestospongia testudinariaMutafuran H
Aspergillus sp. LS78Aspericacid A–B
DiterpenesDendrillamembranosa(+)-Darwinolide
TriterpenesRhabdastrella sp.Rhabdastins H–I
MeroterpenesNew CaledonianAlisiaquinones A–C
Alisiaquinol
Substituted THFPachastrissa/Jaspis sp.Jaspines A-B
FungiMarinedrugs 20 00642 i005MeroterpenesAlternaria alternataTricycloalterfurenes A–D
Stemphylium sp.Tricycloalterfurenes E–G
Substituted THFMyrothecium sp. BZO-L062(−)-1S-Myrothecol
(−)-1R-Myrothecol
Methoxy-myrothecol
Astrosphaeriella nypae BCC-5335Astronypyrone
Astronyquinone
Astronyurea
Emericella variecolor(+)-Varitriol
(−)-Varitriol
Bacteria
Marinedrugs 20 00642 i006		SesquiterpenesStreptomyces sp. CMB-M0423Heronapyrroles C–D
MeroterpenesStreptomyces sp. AJS-327 and CNQ-253Marinoterpins A–C
Table
Table 2. Summary of most active compounds for a range of bioactivities within this review.
Table 2. Summary of most active compounds for a range of bioactivities within this review.
CompoundBiological ActivityCell Line or OrganismBiological ResultAssayReference
trans-oxylipidNematocidalHaemonchus contortusLD50 = 1.8 ppmParasitic nematode larval development assay[21]
Trichostrongylus colubriformisLD50 = 9.9 ppm
(+)-PMAPheromonePetromyzon marinus10−11 molL−1Electro-olfactogram[26]
Mutafuran DAntifungal activityCryptococcus neoformans var. grubiiMIC = 4 μg/mLPathogenic fungus assay[27]
Furoplocamioid CAntifeedant effectsLeptinotarsa decemlineataEC50 = 19.1 nmol/cm2Insect bioassay[32]
Myzus persicaeEC50 = 3.7 nmol/cm2
Ropalosiphum padiEC50 = 1.6 nmol/cm2
Heranopyrrole DAntibacterial activityStaphylococcus aureus ATCC 25923 IC50 = 1.8 μMAntibacterial assay [36]
Staphylococcus epidermidis ATCC 12228IC50 = 0.9 μM
Bacillus subtilis ATCC 6633IC50 = 1.8 μM
(+)-DarwinolideAntibacterial activityStaphylococcus aureusIC50 = 33.2 μMMRSA biofilm assay[49]
Uprolide D acetateCytotoxic Activity Against Tumor Cell LinesHeLa cellsIC50 = 2.5 µg/ mCytotoxicity assay
on human cells		[52]
CCRF-CEM T-cell leukemia IC50 = 7.0 µg/ mL
HCT 116 colon cancerIC50 = 7.0 µg/ mL
MCF-7 breast adenocarcinomaIC50 = 0.6 µg/ mL
Thyrsenol BCytotoxic Activity Against Tumor Cell LinesMurine lymphoid neoplasm P-388 cellsIC50 = 0.016 μMCytotoxicity assays on human cells[74]
Inhibitory activityProtein phosphatase PP2AInhibition > 90% ([PP2A] > 10 μM)Enzymatic assay[75]
Saiyacenol BAntiproliferative activity Against Tumor Cell LinesMM144 (human multiple myeloma) Jurkat (human T-cell acute leukemia)IC50 = 11.0 μMCytotoxicity assays on human cells[78]
HeLa (human cervical carcinoma)IC50 = 24.5 μM
CADO-ES1 (human Ewing’s sarcoma)IC50 = 14.0 μM
Jurkat (human T-cell acute leukemiaIC50 = 2.7 μM
Antifouling activityNavicula cf. salinicolaIC50 = 17.2 μMDiatom growth inhibition
Cylindrotheca sp.IC50 = 17.0 μMInhibition of macroalgal spore germination
Anti-protozoal activityLeishmania amazonensisIC50 = 10.3 μMIn vitro susceptibility assay[80]
28-iodo-saiyacenol BAnti-protozoal activityLeishmania amazonensisIC50 = 5.4 μMIn vitro susceptibility assay[80]
Alisiaquinone CAntimalarial activity
(in vitro)		MC29 CQRIC50 = 0.08 μM[3H]-
Hypoxanthine incorporation		[90]
B1 CQRIC50 = 0.21 μM
F32 CQSIC50 = 0.15 μM
Antimalarial activity
(in vivo)		Rodent malariaMortality day 5 = 0 (5 mg/kg/day)
Mortality day 5 = 80 (20 mg/kg/day)		four-day suppressive in vivo assay
(−)-1S-MyrothecolAntioxidant activity EC50 = 1.2 µg/mLABTS assay[100]
μM Trolox Equiv/μM = 1.4ORAC assay
(+)-1R-MyrothecolAntioxidant activity EC50 = 1.4 µg/mLABTS assay
μM Trolox Equiv/μM = 1.2ORAC assay
(+)-VaritriolCytotoxic activity to cancer cell lines RXF-393 (Renal cancer cell)GI50 = 0.16 μMCytotoxicity assays[104]
SNB-75 (CNS cancer cell)GI50 = 0.24 μMCytotoxicity assays
DU-145 (breast cancer cell)GI50 = 0.11 μMCytotoxicity assays
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González-Andrés, P.; Fernández-Peña, L.; Díez-Poza, C.; Barbero, A. The Tetrahydrofuran Motif in Marine Lipids and Terpenes. Mar. Drugs 2022, 20, 642. https://doi.org/10.3390/md20100642

AMA Style

González-Andrés P, Fernández-Peña L, Díez-Poza C, Barbero A. The Tetrahydrofuran Motif in Marine Lipids and Terpenes. Marine Drugs. 2022; 20(10):642. https://doi.org/10.3390/md20100642

Chicago/Turabian Style

González-Andrés, Paula, Laura Fernández-Peña, Carlos Díez-Poza, and Asunción Barbero. 2022. "The Tetrahydrofuran Motif in Marine Lipids and Terpenes" Marine Drugs 20, no. 10: 642. https://doi.org/10.3390/md20100642

APA Style

González-Andrés, P., Fernández-Peña, L., Díez-Poza, C., & Barbero, A. (2022). The Tetrahydrofuran Motif in Marine Lipids and Terpenes. Marine Drugs, 20(10), 642. https://doi.org/10.3390/md20100642

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