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22 pages, 2951 KiB

Open AccessArticle

Design, Synthesis and In Vitro Investigation of Novel Basic Celastrol Carboxamides as Bio-Inspired Leishmanicidal Agents Endowed with Inhibitory Activity against Leishmania Hsp90

by Ivan Bassanini, Silvia Parapini, Erica E. Ferrandi, Elena Gabriele, Nicoletta Basilico, Donatella Taramelli and Anna Sparatore

Biomolecules 2021, 11(1), 56; https://doi.org/10.3390/biom11010056 - 5 Jan 2021

Cited by 15 | Viewed by 3053

Abstract

The natural triterpene celastrol (CE) is here used as lead compound for the design and synthesis of a panel of eleven CE carboxamides that were tested in vitro for their growth inhibitory activity against Leishmania infantum and L.tropica parasites. Among [...] Read more.

The natural triterpene celastrol (CE) is here used as lead compound for the design and synthesis of a panel of eleven CE carboxamides that were tested in vitro for their growth inhibitory activity against Leishmania infantum and L.tropica parasites. Among them, in vitro screening identified four basic CE carboxamides endowed with nanomolar leishmanicidal activity, against both the promastigotes and the intramacrophage Leishmania amastigotes forms. These compounds also showed low toxicity toward two human (HMEC-1 and THP-1) and one murine (BMDM) cell lines. Interestingly, the most selective CE analogue (compound 3) was also endowed with the ability to inhibit the ATPase activity of the Leishmania protein chaperone Hsp90 as demonstrated by the in vitro assay conducted on a purified, full-length recombinant protein. Preliminary investigations by comparing it with the naturally occurring Hsp90 active site inhibitor Geldanamycin (GA) in two different in vitro experiments were performed. These promising results set the basis for a future biochemical investigation of the mode of interaction of celastrol and CE-inspired compounds with Leishmania Hsp90. Full article

(This article belongs to the Special Issue Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases)

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12 pages, 2503 KiB

Open AccessCommunication

Synthesis and Antiplasmodial Activity of Novel Bioinspired Imidazolidinedione Derivatives

by Anna Jaromin, Anna Czopek, Silvia Parapini, Nicoletta Basilico, Ernest Misiak, Jerzy Gubernator and Agnieszka Zagórska

Biomolecules 2021, 11(1), 33; https://doi.org/10.3390/biom11010033 - 29 Dec 2020

Cited by 7 | Viewed by 2857

Abstract

Malaria is an enormous threat to public health, due to the emergence of Plasmodium falciparum resistance to widely-used antimalarials, such as chloroquine (CQ). Current antimalarial drugs are aromatic heterocyclic derivatives, most often containing a basic component with an added alkyl chain in their [...] Read more.

Malaria is an enormous threat to public health, due to the emergence of Plasmodium falciparum resistance to widely-used antimalarials, such as chloroquine (CQ). Current antimalarial drugs are aromatic heterocyclic derivatives, most often containing a basic component with an added alkyl chain in their chemical structure. While these drugs are effective, they have many side effects. This paper presents the synthesis and preliminary physicochemical characterisation of novel bioinspired imidazolidinedione derivatives, where the imidazolidinedione core was linked via the alkylene chain and the basic piperazine component to the bicyclic system. These compounds were tested against the asexual stages of two strains of P. falciparum—the chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains. In parallel, in vitro cytotoxicity was investigated on a human keratinocyte cell line, as well as their hemolytic activity. The results demonstrated that the antiplasmodial effects were stronger against the W2 strain (IC₅₀ between 2424.15–5648.07 ng/mL (4.98–11.95 µM)), compared to the D10 strain (6202.00–9659.70 ng/mL (12.75–19.85 µM)). These molecules were also non-hemolytic to human erythrocytes at a concentration active towards the parasite, but with low toxicity to mammalian cell line. The synthetized derivatives, possessing enhanced antimalarial activity against the CQ-resistant strain of P. falciparum, appear to be interesting antimalarial drug candidates. Full article

(This article belongs to the Special Issue Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases)

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14 pages, 3565 KiB

Open AccessFeature PaperArticle

Furan-Conjugated Tripeptides as Potent Antitumor Drugs

by Hunain Ali, Almas Jabeen, Rukesh Maharjan, Muhammad Nadeem-ul-Haque, Husena Aamra, Salma Nazir, Serab Khan, Hamza Olleik, Marc Maresca and Farzana Shaheen

Biomolecules 2020, 10(12), 1684; https://doi.org/10.3390/biom10121684 - 16 Dec 2020

Cited by 18 | Viewed by 4377

Abstract

Cervical cancer is among the leading causes of death in women. Chemotherapy options available for cervical cancer include highly cytotoxic drugs such as taxol, cisplatin, 5-florouracil, and doxorubicin, which are not specific. In the current study, we have identified a new peptide conjugate [...] Read more.

Cervical cancer is among the leading causes of death in women. Chemotherapy options available for cervical cancer include highly cytotoxic drugs such as taxol, cisplatin, 5-florouracil, and doxorubicin, which are not specific. In the current study, we have identified a new peptide conjugate (Fur⁴-2-Nal³-Ala²-Phe¹-CONH₂) (conjugate 4), from screening of a small library of tripeptide-conjugates of furan, as highly potent anticancer compound against human cervical cancer cells (HeLa cells) (IC₅₀ = 0.15 ± 0.05 µg/mL or 0.28 +/− 0.09 µM). Peptides were constructed on Rink amide resin from C- to N-terminus followed by capping by α-furoic acid moiety. The synthesized peptides were purified by recycling RP-HPLC, and structures of all the peptides were confirmed by using FABMS/ESIMS, ¹H- NMR, ¹³C-NMR, and HR-FABMS. Conjugate 4 was furthermore found to be specifically active against human cervical cancer cells since it did not inhibit the proliferation of other human normal cells (HUVEC (human umbilical vein endothelial cells) and IMR-90 (normal human fibroblasts)), and cancer cells tested (HUVEC, MCF-7, and MDA-MB-231 cells), as well as in mice 3T3 cells (normal fibroblasts). This study revealed a good structure activity relationship of various peptide conjugates. Conjugate 4 in branched forms (4a and 4b) were also synthesized and evaluated against HeLa cells, and results revealed that both were inactive. Atomic force microscopy (AFM) studies and staining with rhodamine 123 and propidium iodide (PI) revealed that conjugate 4 possesses a membranolytic effect and causes the loss of mitochondrial membrane potential. Full article

(This article belongs to the Special Issue Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases)

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10 pages, 1439 KiB

Open AccessArticle

Anti-cancer Evaluation of Depsides Isolated from Indonesian Folious Lichens: Physcia millegrana, Parmelia dilatata and Parmelia aurulenta

by Ari Satia Nugraha, Tinton Agung Laksono, Lilla Nur Firli, Chintya Permata Zahky Sukrisno Putri, Dwi Koko Pratoko, Zulfikar Zulfikar, Ludmilla Fitri Untari, Hendris Wongso, Jacob M. Lambert, Carolyn T. Dillon and Paul A. Keller

Biomolecules 2020, 10(10), 1420; https://doi.org/10.3390/biom10101420 - 8 Oct 2020

Cited by 12 | Viewed by 3885

Abstract

Cancer is a serious health burden on global societies. The discovery and development of new anti-cancer therapies remains a challenging objective. Although it has been shown that lichen secondary metabolites may be potent sources for new anti-cancer agents, the Indonesian- grown folious lichens, [...] Read more.

Cancer is a serious health burden on global societies. The discovery and development of new anti-cancer therapies remains a challenging objective. Although it has been shown that lichen secondary metabolites may be potent sources for new anti-cancer agents, the Indonesian- grown folious lichens, Physcia millegrana, Parmelia dilatata and Parmeila aurulenta, have not yet been explored. In this study exhaustive preparative high-performance liquid chromatography was employed to isolate the lichen constituents with spectroscopic and spectrometric protocols identifying nine depsides 9–17, including the new methyl 4-formyl-2,3-dihydroxy-6-methylbenzoate 13. The cytotoxicity of the depsides towards cancer cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results indicated lowest toxicity of the depsides towards human A549 lung cancer cells. Importantly, the di-depsides (11, 12 and 17) showed greatest toxicity, indicating that these structures are biologically more active than the mono-depsides against the HepG2 liver cancer, A549 lung cancer and HL-60 leukemia cell lines. Full article

(This article belongs to the Special Issue Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases)

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22 pages, 7728 KiB

Open AccessArticle

A Diamine-PEGylated Oleanolic Acid Derivative Induced Efficient Apoptosis through a Death Receptor and Mitochondrial Apoptotic Pathway in HepG2 Human Hepatoma Cells

by Fatin Jannus, Marta Medina-O’Donnell, Francisco Rivas, Luis Díaz-Ruiz, Eva E. Rufino-Palomares, José A. Lupiáñez, Andrés Parra and Fernando J. Reyes-Zurita

Biomolecules 2020, 10(10), 1375; https://doi.org/10.3390/biom10101375 - 28 Sep 2020

Cited by 19 | Viewed by 2940

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Our recent studies have shown that the diamine-(PEG)ylated oleanolic acid (OADP) has strong anti-tumor effects in HCCs. In this study, we evaluated the anti-tumor mechanisms of OADP in the HepG2 HCC cell [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Our recent studies have shown that the diamine-(PEG)ylated oleanolic acid (OADP) has strong anti-tumor effects in HCCs. In this study, we evaluated the anti-tumor mechanisms of OADP in the HepG2 HCC cell line. The cytotoxicity results showed that HepG2 cell viability was markedly reduced, with a very low 50% of cell growth inhibitory concentration (IC₅₀, 0.14 µg/mL). We then investigated the anti-tumor mechanisms of OADP in HepG2 cells. The flow-cytometry analysis was used to evaluate cell apoptosis, indicating that 74–95% of cells were apoptotic. OADP caused cell cycle arrest in the G0/G1 phase and the loss of the mitochondrial membrane potential (MMP). Western blot analysis was performed to assess the expression levels of key proteins associated with the underlying molecular mechanism. The results showed the clear upregulation of caspase-8, caspase-9, caspase-3, Bak, p21, and p53, accompanied by the downregulation of Bcl-2. Similar results were obtained by the cotreatment with OADP and the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Agents such as OADP, which are capable of activating extrinsic and intrinsic apoptotic pathways, may represent potential HCC cancer therapies. Full article

(This article belongs to the Special Issue Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases)

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16 pages, 1682 KiB

Open AccessArticle

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

by Annalisa Pecoraro, Antonella Virgilio, Veronica Esposito, Aldo Galeone, Giulia Russo and Annapina Russo

Biomolecules 2020, 10(4), 583; https://doi.org/10.3390/biom10040583 - 10 Apr 2020

Cited by 21 | Viewed by 3120

Abstract

The antiproliferative G-quadruplex aptamers are a promising and challenging subject in the framework of the anticancer therapeutic oligonucleotides research field. Although several antiproliferative G-quadruplex aptamers have been identified and proven to be effective on different cancer cell lines, their mechanism of action is [...] Read more.

The antiproliferative G-quadruplex aptamers are a promising and challenging subject in the framework of the anticancer therapeutic oligonucleotides research field. Although several antiproliferative G-quadruplex aptamers have been identified and proven to be effective on different cancer cell lines, their mechanism of action is still unexplored. We have recently described the antiproliferative activity of a heterochiral thrombin binding aptamer (TBA) derivative, namely, LQ1. Here, we investigate the molecular mechanisms of LQ1 activity and the structural and antiproliferative properties of two further TBA derivatives, differing from LQ1 only by the small loop base-compositions. We demonstrate that in p53 deleted colon cancer cells, LQ1 causes nucleolar stress, impairs ribosomal RNA processing, leading to the accumulation of pre-ribosomal RNAs, arrests cells in the G2/M phase and induces early apoptosis. Importantly, the depletion of uL3 abrogates all these effects, indicating that uL3 is a crucial player in the mechanism of action of LQ1. Taken together, our findings identify p53-independent and uL3-dependent nucleolar stress as a novel stress response pathway activated by a specific G-quadruplex TBA derivative. To the best of our knowledge, this investigation reveals, for the first time, the involvement of the nucleolar stress pathway in the mechanism of action of antiproliferative G-quadruplex aptamers. Full article

(This article belongs to the Special Issue Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases)

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Review

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61 pages, 36395 KiB

Open AccessReview

Meroterpenoids: A Comprehensive Update Insight on Structural Diversity and Biology

by Mamona Nazir, Muhammad Saleem, Muhammad Imran Tousif, Muhammad Aijaz Anwar, Frank Surup, Iftikhar Ali, Daijie Wang, Nilufar Z. Mamadalieva, Elham Alshammari, Mohamed L. Ashour, Ahmed M. Ashour, Ishtiaq Ahmed, Elizbit, Ivan R. Green and Hidayat Hussain

Biomolecules 2021, 11(7), 957; https://doi.org/10.3390/biom11070957 - 29 Jun 2021

Cited by 57 | Viewed by 7027

Abstract

Meroterpenoids are secondary metabolites formed due to mixed biosynthetic pathways which are produced in part from a terpenoid co-substrate. These mixed biosynthetically hybrid compounds are widely produced by bacteria, algae, plants, and animals. Notably amazing chemical diversity is generated among meroterpenoids via a [...] Read more.

Meroterpenoids are secondary metabolites formed due to mixed biosynthetic pathways which are produced in part from a terpenoid co-substrate. These mixed biosynthetically hybrid compounds are widely produced by bacteria, algae, plants, and animals. Notably amazing chemical diversity is generated among meroterpenoids via a combination of terpenoid scaffolds with polyketides, alkaloids, phenols, and amino acids. This review deals with the isolation, chemical diversity, and biological effects of 452 new meroterpenoids reported from natural sources from January 2016 to December 2020. Most of the meroterpenoids possess antimicrobial, cytotoxic, antioxidant, anti-inflammatory, antiviral, enzyme inhibitory, and immunosupressive effects. Full article

(This article belongs to the Special Issue Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases)

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16 pages, 1303 KiB

Open AccessReview

Therapeutic Potential of Ursonic Acid: Comparison with Ursolic Acid

by Juhyeon Son and Sang Yeol Lee

Biomolecules 2020, 10(11), 1505; https://doi.org/10.3390/biom10111505 - 2 Nov 2020

Cited by 39 | Viewed by 5373

Abstract

Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as Ziziphus jujuba. Since the pharmacological effects and associated mechanisms of UNA are not well-known, [...] Read more.

Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as Ziziphus jujuba. Since the pharmacological effects and associated mechanisms of UNA are not well-known, in this work, we attempt to introduce the therapeutic potential of UNA with a comparison to ursolic acid (ULA), a well-known secondary metabolite, for beneficial effects. UNA has a keto group at the C-3 position, which may provide a critical difference for the varied biological activities between UNA and ULA. Several studies previously showed that UNA exerts pharmaceutical effects similar to, or stronger than, ULA, with UNA significantly decreasing the survival and proliferation of various types of cancer cells. UNA has potential to exert inhibitory effects in parasitic protozoa that cause several tropical diseases. UNA also exerts other potential effects, including antihyperglycemic, anti-inflammatory, antiviral, and antioxidant activities. Of note, a recent study highlighted the suppressive potential of UNA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular modifications of UNA may enhance bioavailability, which is crucial for in vivo and clinical studies. In conclusion, UNA has promising potential to be developed in anticancer and antiprotozoan pharmaceuticals. In-depth investigations may increase the possibility of UNA being developed as a novel reagent for chemotherapy. Full article

(This article belongs to the Special Issue Bio-Inspired Antiproliferative Molecules for the Treatment of Protozoan and/or Cancer Diseases)

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