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33 pages, 2168 KiB

Open AccessReview

Marine-Derived Leads as Anticancer Candidates by Disrupting Hypoxic Signaling through Hypoxia-Inducible Factors Inhibition

by Maria Rita Garcia, Paula B. Andrade, Florence Lefranc and Nelson G. M. Gomes

Mar. Drugs 2024, 22(4), 143; https://doi.org/10.3390/md22040143 - 23 Mar 2024

Cited by 6 | Viewed by 3161

Abstract

The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as [...] Read more.

The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as druggable pivotal players orchestrating tumor metastasis and angiogenesis, thus positioning them as prime targets for cancer treatment. A range of HIF inhibitors, notably natural compounds originating from marine organisms, exhibit encouraging anticancer properties, underscoring their significance as promising therapeutic options. Bioprospection of the marine environment is now a well-settled approach to the discovery and development of anticancer agents that might have their medicinal chemistry developed into clinical candidates. However, despite the massive increase in the number of marine natural products classified as ‘anticancer leads,’ most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)

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13 pages, 3854 KiB

Open AccessReview

Carbonic Anhydrase Inhibitors from Marine Natural Products

by Claudiu T. Supuran

Mar. Drugs 2022, 20(11), 721; https://doi.org/10.3390/md20110721 - 17 Nov 2022

Cited by 24 | Viewed by 3322

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes in organisms in all life kingdoms, being involved in pH regulation, metabolic processes and many other physiological and pathological conditions. CA inhibitors and activators thus possess applications as pharmacological agents in the management of a [...] Read more.

Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes in organisms in all life kingdoms, being involved in pH regulation, metabolic processes and many other physiological and pathological conditions. CA inhibitors and activators thus possess applications as pharmacological agents in the management of a range of diseases. Marine natural products have allowed the identification of some highly interesting CA inhibitors, among which are sulfonamides, phenols, polyamines, coumarins and several other miscellaneous inhibitors, which are reviewed here. Psammaplin C and some bromophenols were the most investigated classes of such marine-based inhibitors and have been used as lead molecules for developing interesting types of potent and, in some cases, isoform-selective inhibitors, with applications as antitumor agents by inhibiting human CA XII and P-glycoprotein activities. Some phenols have shown interesting bacterial and fungal β-CA inhibitory effects. Marine natural products thus constitute a gold mine for identifying novel CA inhibitors, some of which may lead to the development of novel types of pharmacological agents. Full article

(This article belongs to the Special Issue The Mechanisms of Action of Bioactive Marine Natural Products)

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22 pages, 3144 KiB

Open AccessArticle

Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells

by Immacolata Maietta, Amparo Martínez-Pérez, Rosana Álvarez, Ángel R. De Lera, África González-Fernández and Rosana Simón-Vázquez

Pharmaceuticals 2022, 15(7), 824; https://doi.org/10.3390/ph15070824 - 2 Jul 2022

Cited by 18 | Viewed by 4858

Abstract

Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and metastasis of pancreatic ductal adenocarcinoma (PDAC). Thus, epigenetic enzyme inhibitors could be the key to revert those events and transform PDAC into a drug-sensitive tumor. We performed a [...] Read more.

Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and metastasis of pancreatic ductal adenocarcinoma (PDAC). Thus, epigenetic enzyme inhibitors could be the key to revert those events and transform PDAC into a drug-sensitive tumor. We performed a systematic study with five different epigenetic enzyme inhibitors (1, UVI5008, MS275, psammaplin A, and BIX01294) targeting either Histone Deacetylase (HDAC) 1 or 1/4, DNA methyltransferase 3a (DNMT3a), Euchromatic histone lysine methyltransferase 2 (EHMT2), or Sirtuin 1 (SIRT1), as well as one drug that restores the p53 function (P53R3), in three different human PDAC cell lines (SKPC-1, MIA PaCa-2, and BxPC-3) using 2D and 3D cell cultures. The synergistic effect of these antitumoral drugs with gemcitabine was tested and the most efficient combinations were characterized by RNA-seq. The inhibition of HDAC1/4 (MS275), HDAC1/4/SIRT1/DNMT3a (UVI5008) or EHMT2 (BIX01294) induced a significant reduction on the cell viability, even in gemcitabine-resistance cells. The combination of UVI5008 or MS275 with gemcitabine induced a synergistic effect at low concentration and the RNA-Seq analysis revealed some synergy candidate genes as potential biomarkers. Reverting aberrant epigenetic modifications in combination with gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs)

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17 pages, 2673 KiB

Open AccessArticle

Inhibition of the Quorum Sensing System, Elastase Production and Biofilm Formation in Pseudomonas aeruginosa by Psammaplin A and Bisaprasin

by Emmanuel T. Oluwabusola, Nursheena Parveen Katermeran, Wee Han Poh, Teo Min Ben Goh, Lik Tong Tan, Oluwatofunmilayo Diyaolu, Jioji Tabudravu, Rainer Ebel, Scott A. Rice and Marcel Jaspars

Molecules 2022, 27(5), 1721; https://doi.org/10.3390/molecules27051721 - 6 Mar 2022

Cited by 18 | Viewed by 5099

Abstract

Natural products derived from marine sponges have exhibited bioactivity and, in some cases, serve as potent quorum sensing inhibitory agents that prevent biofilm formation and attenuate virulence factor expression by pathogenic microorganisms. In this study, the inhibitory activity of the psammaplin-type compounds, psammaplin [...] Read more.

Natural products derived from marine sponges have exhibited bioactivity and, in some cases, serve as potent quorum sensing inhibitory agents that prevent biofilm formation and attenuate virulence factor expression by pathogenic microorganisms. In this study, the inhibitory activity of the psammaplin-type compounds, psammaplin A (1) and bisaprasin (2), isolated from the marine sponge, Aplysinellarhax, are evaluated in quorum sensing inhibitory assays based on the Pseudomonas aeruginosa PAO1 lasB-gfp(ASV) and rhlA-gfp(ASV) biosensor strains. The results indicate that psammaplin A (1) showed moderate inhibition on lasB-gfp expression, but significantly inhibited the QS-gene promoter, rhlA-gfp, with IC₅₀ values at 14.02 μM and 4.99 μM, respectively. In contrast, bisaprasin (2) displayed significant florescence inhibition in both biosensors, PAO1 lasB-gfp and rhlA-gfp, with IC₅₀ values at 3.53 μM and 2.41 μM, respectively. Preliminary analysis suggested the importance of the bromotyrosine and oxime functionalities for QSI activity in these molecules. In addition, psammaplin A and bisaprasin downregulated elastase expression as determined by the standard enzymatic elastase assay, although greater reduction in elastase production was observed with 1 at 50 μM and 100 μM. Furthermore, the study revealed that bisaprasin (2) reduced biofilm formation in P. aeruginosa. Full article

(This article belongs to the Special Issue Natural Products: From Isolation and Identification to Biological Activity—Second Edition)

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22 pages, 6766 KiB

Open AccessReview

Marine-Derived Natural Lead Compound Disulfide-Linked Dimer Psammaplin A: Biological Activity and Structural Modification

by Qinxue Jing, Xu Hu, Yanzi Ma, Jiahui Mu, Weiwei Liu, Fanxing Xu, Zhanlin Li, Jiao Bai, Huiming Hua and Dahong Li

Mar. Drugs 2019, 17(7), 384; https://doi.org/10.3390/md17070384 - 27 Jun 2019

Cited by 35 | Viewed by 6268

Abstract

Marine natural products are considered to be valuable resources that are furnished with diverse chemical structures and various bioactivities. To date, there are seven compounds derived from marine natural products which have been approved as therapeutic drugs by the U.S. Food and Drug [...] Read more.

Marine natural products are considered to be valuable resources that are furnished with diverse chemical structures and various bioactivities. To date, there are seven compounds derived from marine natural products which have been approved as therapeutic drugs by the U.S. Food and Drug Administration. Numerous bromotyrosine derivatives have been isolated as a type of marine natural products. Among them, psammaplin A, including the oxime groups and carbon–sulfur bonds, was the first identified symmetrical bromotyrosine-derived disulfide dimer. It has been found to have a broad bioactive spectrum, especially in terms of antimicrobial and antiproliferative activities. The highest potential indole-derived psammaplin A derivative, UVI5008, is used as an epigenetic modulator with multiple enzyme inhibitory activities. Inspired by these reasons, psammaplin A has gradually become a research focus for pharmacologists and chemists. To the best of our knowledge, there is no systematic review about the biological activity and structural modification of psammaplin A. In this review, the pharmacological effects, total synthesis, and synthesized derivatives of psammaplin A are summarized. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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13 pages, 1048 KiB

Open AccessArticle

Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A

by Bingbing Zhang, Guangsheng Shan, Yinying Zheng, Xiaolin Yu, Zhu-Wei Ruan, Yang Li and Xinsheng Lei

Mar. Drugs 2019, 17(6), 333; https://doi.org/10.3390/md17060333 - 3 Jun 2019

Cited by 9 | Viewed by 3592

Abstract

Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural [...] Read more.

Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the trans alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities. Inspired by such a structural similarity, we hypothesized the fluoroolefin moiety would mimic both the alkene moiety in Largazole and the amide moiety in Psammaplin A, and thus designed and synthesized two novel fluoro olefin analogs of Largazole. The preliminary biological assays showed that the fluoro analogs possessed comparable Class I HDAC inhibitory effects, indicating that this kind of modification on the side chain of Largazole was tolerable. Full article

(This article belongs to the Special Issue Synthesis of Marine Natural Products and Analogues)

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15 pages, 4650 KiB

Open AccessArticle

Biochemical and Anti-Triple Negative Metastatic Breast Tumor Cell Properties of Psammaplins

by Yu-Dong Zhou, Jun Li, Lin Du, Fakhri Mahdi, Thuy P. Le, Wei-Lun Chen, Steven M. Swanson, Kounosuke Watabe and Dale G. Nagle

Mar. Drugs 2018, 16(11), 442; https://doi.org/10.3390/md16110442 - 10 Nov 2018

Cited by 18 | Viewed by 4789

Abstract

Breast tumors reprogram their cellular metabolism, nutrient uptake, and utilization-associated biochemical processes. These processes become further transformed as genetically predisposed metastatic breast tumor cells colonize specific organs. Breast tumor cells often metastasize to the brain, bone, lung and liver. Massagué and colleagues isolated [...] Read more.

Breast tumors reprogram their cellular metabolism, nutrient uptake, and utilization-associated biochemical processes. These processes become further transformed as genetically predisposed metastatic breast tumor cells colonize specific organs. Breast tumor cells often metastasize to the brain, bone, lung and liver. Massagué and colleagues isolated organotropic subclones and established organ-specific gene signatures associated with lung-, bone-, and brain-specific metastatic triple-negative breast cancer (TNBC) MDA-MB-231 cells. Using these genetically characterized metastatic subclones specific to lung (LM4175), bone (BoM1833), and brain (BrM-2a), we evaluated marine natural products for the ability to differentially suppress metastatic breast cancer cells in a target organ-dependent manner. Psammaplin-based histone deacetylase (HDAC) inhibitors were found to differentially inhibit HDAC activity, induce activation of hypoxia-inducible factor-1 (HIF-1), and disrupt organotropic metastatic TNBC subclone growth. Further, psammaplins distinctly suppressed the outgrowth of BoM1833 tumor spheroids in 3D-culture systems. Similar results were observed with the prototypical HDAC inhibitor trichostatin A (TSA). These organotropic tumor cell-based studies suggest the potential application of HDAC inhibitors that may yield new directions for anti-metastatic breast tumor research and drug discovery. Full article

(This article belongs to the Special Issue Bioactive Compounds from Marine Sponges)

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38 pages, 8189 KiB

Open AccessReview

Anticancer Activity of Natural Compounds from Plant and Marine Environment

by Anna Lichota and Krzysztof Gwozdzinski

Int. J. Mol. Sci. 2018, 19(11), 3533; https://doi.org/10.3390/ijms19113533 - 9 Nov 2018

Cited by 394 | Viewed by 20733

Abstract

This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their properties, mechanisms of action, their structure–activity relationships, along with their anticancer properties and their potential as chemotherapeutic drugs are [...] Read more.

This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their properties, mechanisms of action, their structure–activity relationships, along with their anticancer properties and their potential as chemotherapeutic drugs are discussed in this paper. This paper presents natural substances from plants, animals, and their aquatic environments. These substances include the vinca alkaloids, mistletoe plant extracts, podophyllotoxin derivatives, taxanes, camptothecin, combretastatin, and others including geniposide, colchicine, artesunate, homoharringtonine, salvicine, ellipticine, roscovitine, maytanasin, tapsigargin, and bruceantin. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from the marine plants and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates (e.g., sponges, tunicates, and soft corals) as well as certain other substances that have been tested on cells and experimental animals and used in human chemotherapy. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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13 pages, 2213 KiB

Open AccessCommunication

Identification of Novel HIV-1 Latency-Reversing Agents from a Library of Marine Natural Products

by Khumoekae Richard, David E. Williams, E. Dilip De Silva, Mark A. Brockman, Zabrina L. Brumme, Raymond J. Andersen and Ian Tietjen

Viruses 2018, 10(7), 348; https://doi.org/10.3390/v10070348 - 27 Jun 2018

Cited by 36 | Viewed by 5540

Abstract

Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established in vitro model of HIV-1 latency, we screened 257 pure compounds from a marine natural product library and identified 4 (psammaplin A, [...] Read more.

Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established in vitro model of HIV-1 latency, we screened 257 pure compounds from a marine natural product library and identified 4 (psammaplin A, aplysiatoxin, debromoaplysiatoxin, and previously-described alotaketal C) that induced expression of latent HIV-1 provirus in both cell line and primary cell models. Notably, aplysiatoxin induced similar levels of HIV-1 expression as prostratin but at up to 900-fold lower concentrations and without substantial effects on cell viability. Psammaplin A enhanced HIV-1 expression synergistically when treated in combination with the protein kinase C (PKC) activator prostratin, but not the histone deacetylase inhibitor (HDACi) panobinostat, suggesting that psammaplin A functions as a latency-reversing agent (LRA) of the HDACi class. Conversely, aplysiatoxin and debromoaplysiatoxin synergized with panobinostat but not prostratin, suggesting that they function as PKC activators. Our study identifies new compounds from previously untested marine natural products and adds to the repertoire of LRAs that can inform therapeutic “shock-and-kill”-based strategies to eliminate latent HIV-infected reservoirs. Full article

(This article belongs to the Special Issue Homage to Mark Wainberg)

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19 pages, 1912 KiB

Open AccessArticle

Tumor Protein (TP)-p53 Members as Regulators of Autophagy in Tumor Cells upon Marine Drug Exposure

by Edward A. Ratovitski

Mar. Drugs 2016, 14(8), 154; https://doi.org/10.3390/md14080154 - 16 Aug 2016

Cited by 29 | Viewed by 7745

Abstract

Targeting autophagic pathways might play a critical role in designing novel chemotherapeutic approaches in the treatment of human cancers, and the prevention of tumor-derived chemoresistance. Marine compounds were found to decrease tumor cell growth in vitro and in vivo. Some of them were [...] Read more.

Targeting autophagic pathways might play a critical role in designing novel chemotherapeutic approaches in the treatment of human cancers, and the prevention of tumor-derived chemoresistance. Marine compounds were found to decrease tumor cell growth in vitro and in vivo. Some of them were shown to induce autophagic flux in tumor cells. In this study, we observed that the selected marine life-derived compounds (Chromomycin A2, Psammaplin A, and Ilimaquinone) induce expression of several autophagic signaling intermediates in human squamous cell carcinoma, glioblastoma, and colorectal carcinoma cells in vitro through a transcriptional regulation by tumor protein (TP)-p53 family members. These conclusions were supported by specific qPCR expression analysis, luciferase reporter promoter assay, and chromatin immunoprecipitation of promoter sequences bound to the TP53 family proteins, and silencing of the TP53 members in tumor cells. Full article

(This article belongs to the Special Issue Marine Compounds as Modulators of Autophagy and Lysosomal Activity)

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12 pages, 203 KiB

Open AccessArticle

Synthesis of the Marine Bromotyrosine Psammaplin F and Crystal Structure of a Psammaplin A Analogue

by Qianjiao Yang, Dan Liu, Deyang Sun, Sen Yang, Guodong Hu, Zuti Wu and Linxiang Zhao

Molecules 2010, 15(12), 8784-8795; https://doi.org/10.3390/molecules15128784 - 2 Dec 2010

Cited by 19 | Viewed by 8995

Abstract

Psammaplin F, an unsymmetrical disulfide bromotyrosine, was isolated from the sponge Pseudoceratina purpurea in 2003. We reported here the first total synthesis of psammaplin F in 12% overall yield by employing Cleland’s reagent reduction as key step. The longest linear synthetic sequence starting [...] Read more.

Psammaplin F, an unsymmetrical disulfide bromotyrosine, was isolated from the sponge Pseudoceratina purpurea in 2003. We reported here the first total synthesis of psammaplin F in 12% overall yield by employing Cleland’s reagent reduction as key step. The longest linear synthetic sequence starting from 3-bromo-4-hydroxybenzaldehyde and hydantoin was seven steps. In addition, a detailed X-ray crystal structure analysis of psammaplin A analogue 8b is given for the first time. Full article

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