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Open AccessArticle

Kempopeptin C, a Novel Marine-Derived Serine Protease Inhibitor Targeting Invasive Breast Cancer

by Fatma H. Al-Awadhi, Lilibeth A. Salvador, Brian K. Law, Valerie J. Paul and Hendrik Luesch

Mar. Drugs 2017, 15(9), 290; https://doi.org/10.3390/md15090290 - 16 Sep 2017

Cited by 26 | Viewed by 5464

Kempopeptin C, a novel chlorinated analogue of kempopeptin B, was discovered from a marine cyanobacterium collected from Kemp Channel in Florida. The structure was elucidated using NMR spectroscopy and mass spectrometry (MS). The presence of the basic Lys residue adjacent to the N [...] Read more.

Kempopeptin C, a novel chlorinated analogue of kempopeptin B, was discovered from a marine cyanobacterium collected from Kemp Channel in Florida. The structure was elucidated using NMR spectroscopy and mass spectrometry (MS). The presence of the basic Lys residue adjacent to the N-terminus of the 3-amino-6-hydroxy-2-piperidone (Ahp) moiety contributed to its selectivity towards trypsin and related proteases. The antiproteolytic activity of kempopeptin C was evaluated against trypsin, plasmin and matriptase and found to inhibit these enzymes with IC₅₀ values of 0.19, 0.36 and 0.28 μM, respectively. Due to the significance of these proteases in cancer progression and metastasis, as well as their functional redundancy with respect to targeting overlapping substrates, we examined the effect of kempopeptin C on the downstream cellular substrates of matriptase: CDCP1 and desmoglein-2 (Dsg-2). Kempopeptin C was shown to inhibit the cleavage of both substrates in vitro. Additionally, kempopeptin C reduced the cleavage of CDCP1 in MDA-MB-231 cells up to 10 µM. The functional relevance of targeting matriptase and related proteases was investigated by assessing the effect of kempopeptin C on the migration of breast cancer cells. Kempopeptin C inhibited the migration of the invasive MDA-MB-231 cells by 37 and 60% at 10 and 20 µM, respectively. Full article

(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)

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3148 KiB

Open AccessArticle

Chemistry and Selective Tumor Cell Growth Inhibitory Activity of Polyketides from the South China Sea Sponge Plakortis sp.

by Jiao Li, Cui Li, Raffaele Riccio, Gianluigi Lauro, Giuseppe Bifulco, Tie-Jun Li, Hua Tang, Chun-Lin Zhuang, Hao Ma, Peng Sun and Wen Zhang

Mar. Drugs 2017, 15(5), 129; https://doi.org/10.3390/md15050129 - 03 May 2017

Cited by 11 | Viewed by 4973

Abstract

Simplextone E (1), a new metabolite of polyketide origin, was isolated with eight known analogues (2–9) from the South China Sea sponge Plakortis sp. The relative configuration of the new compound was elucidated by a detailed analysis [...] Read more.

Simplextone E (1), a new metabolite of polyketide origin, was isolated with eight known analogues (2–9) from the South China Sea sponge Plakortis sp. The relative configuration of the new compound was elucidated by a detailed analysis of the spectroscopic data and quantum mechanical calculation of NMR chemical shifts, aided by the newly reported DP4+ approach. Its absolute configuration was determined by the TDDFT/ECD calculation. Simplextone E (1) is proven to be one of the isomers of simplextone D. The absolute configuration at C-8 in alkyl chain of plakortone Q (2) was also assigned based on the NMR calculation. In the preliminary in vitro bioassay, compounds 6 and 7 showed a selective growth inhibitory activity against HCT-116 human colon cancer cells with IC₅₀ values of 8.3 ± 2.4 and 8.4 ± 2.3 μM, corresponding to that of the positive control, adriamycin (IC₅₀ 4.1 μM). The two compounds also showed selective activities towards MCF-7 human breast cancer and K562 human erythroleukemia cells while compound 3 only displayed weak activity against K562 cells. Full article

(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)

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1817 KiB

Open AccessFeature PaperArticle

Laucysteinamide A, a Hybrid PKS/NRPS Metabolite from a Saipan Cyanobacterium, cf. Caldora penicillata

by Chen Zhang, C. Benjamin Naman, Niclas Engene and William H. Gerwick

Mar. Drugs 2017, 15(4), 121; https://doi.org/10.3390/md15040121 - 14 Apr 2017

Cited by 17 | Viewed by 5573

Abstract

A bioactivity guided study of a cf. Caldora penicillata species, collected during a 2013 expedition to the Pacific island of Saipan, Northern Mariana Islands (a commonwealth of the USA), led to the isolation of a new thiazoline-containing alkaloid, laucysteinamide A (1). [...] Read more.

A bioactivity guided study of a cf. Caldora penicillata species, collected during a 2013 expedition to the Pacific island of Saipan, Northern Mariana Islands (a commonwealth of the USA), led to the isolation of a new thiazoline-containing alkaloid, laucysteinamide A (1). Laucysteinamide A is a new monomeric analogue of the marine cyanobacterial metabolite, somocystinamide A (2), a disulfide-bonded dimeric compound that was isolated previously from a Fijian marine cyanobacterium. The structure and absolute configuration of laucysteinamide A (1) was determined by a detailed analysis of its NMR, MS, and CD spectra. In addition, the highly bioactive lipid, curacin D (3), was also found to be present in this cyanobacterial extract. The latter compound was responsible for the potent cytotoxicity of this extract to H-460 human non-small cell lung cancer cells in vitro. Full article

(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)

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2631 KiB

Open AccessFeature PaperArticle

Another Look at Pyrroloiminoquinone Alkaloids—Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues

by Sheng Lin, Erin P. McCauley, Nicholas Lorig-Roach, Karen Tenney, Cassandra N. Naphen, Ai-Mei Yang, Tyler A. Johnson, Thalia Hernadez, Ramandeep Rattan, Frederick A. Valeriote and Phillip Crews

Mar. Drugs 2017, 15(4), 98; https://doi.org/10.3390/md15040098 - 29 Mar 2017

Cited by 18 | Viewed by 5073

Abstract

This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from [...] Read more.

This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from various regions of the Indo-Pacific, known compounds were obtained consisting of nine makaluvamine and three damirone analogues. Four new acetylated derivatives were also prepared. High-accuracy electrospray ionization mass spectrometry (HAESI-MS) m/z ions produced through MS² runs were obtained and interpreted to provide a rapid way for dereplicating isomers containing a pyrrolo[4,3,2-de]quinoline core. In vitro human pancreas/duct epithelioid carcinoma (PANC-1) cell line IC₅₀ data was obtained for 16 compounds and two therapeutic standards. These results along with data gleaned from the literature provided useful structure activity relationship conclusions. Three structural motifs proved to be important in maximizing potency against PANC-1: (i) conjugation within the core of the ABC-ring; (ii) the presence of a positive charge in the C-ring; and (iii) inclusion of a 4-ethyl phenol or 4-ethyl phenol acetate substituent off the B-ring. Two compounds, makaluvamine J (9) and 15-O-acetyl makaluvamine J (15), contained all three of these frameworks and exhibited the best potency with IC₅₀ values of 54 nM and 81 nM, respectively. These two most potent analogs were then tested against the OVCAR-5 cell line and the presence of the acetyl group increased the potency 14-fold from that of 9 whose IC₅₀ = 120 nM vs. that of 15 having IC₅₀ = 8.6 nM. Full article

(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)

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3742 KiB

Open AccessArticle

Characterization and Potential Antitumor Activity of Polysaccharide from Gracilariopsis lemaneiformis

by Yani Kang, Zhi-Jiang Wang, Dongsheng Xie, Xue Sun, Wenge Yang, Xiaodong Zhao and Nianjun Xu

Mar. Drugs 2017, 15(4), 100; https://doi.org/10.3390/md15040100 - 29 Mar 2017

Cited by 66 | Viewed by 5609

Abstract

Substances with valuable antitumor properties have been identified in many marine algae, including an edible polysaccharide from the marine alga Gracilariopsis lemaneiformis (PGL). We previously reported transcriptome profiling data showing that PGL induced transcriptional alterations generate anti-lung cancer activity. To identify how PGL [...] Read more.

Substances with valuable antitumor properties have been identified in many marine algae, including an edible polysaccharide from the marine alga Gracilariopsis lemaneiformis (PGL). We previously reported transcriptome profiling data showing that PGL induced transcriptional alterations generate anti-lung cancer activity. To identify how PGL is detrimental to tumors, we purified PGL to characterize its chemical composition, molecular weight, and sugar and protein content and investigated its antitumor activity. We demonstrated that PGL exerted its antitumor activities by modulating cell viability, morphology, apoptosis, and the apoptosis-related Fas/FasL signaling pathway in the human lung cancer cell line A549, the gastric cancer cell line MKN28, and the mouse melanoma cell line B16. Our data provide the first evidence that PGL inhibits cell proliferation by inducing apoptosis, which is largely mediated by Fas/FasL in cancer cells, suggesting that PGL might be a novel therapeutic agent against cancer. Full article

(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)

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2182 KiB

Open AccessFeature PaperArticle

FUSION-Guided Hypothesis Development Leads to the Identification of N⁶,N⁶-Dimethyladenosine, a Marine-Derived AKT Pathway Inhibitor

by Rachel M. Vaden, Nathaniel W. Oswald, Malia B. Potts, John B. MacMillan and Michael A. White

Mar. Drugs 2017, 15(3), 75; https://doi.org/10.3390/md15030075 - 15 Mar 2017

Cited by 13 | Viewed by 5172

Abstract

Chemicals found in nature have evolved over geological time scales to productively interact with biological molecules, and thus represent an effective resource for pharmaceutical development. Marine-derived bacteria are rich sources of chemically diverse, bioactive secondary metabolites, but harnessing this diversity for biomedical benefit [...] Read more.

Chemicals found in nature have evolved over geological time scales to productively interact with biological molecules, and thus represent an effective resource for pharmaceutical development. Marine-derived bacteria are rich sources of chemically diverse, bioactive secondary metabolites, but harnessing this diversity for biomedical benefit is limited by challenges associated with natural product purification and determination of biochemical mechanism. Using Functional Signature Ontology (FUSION), we report the parallel isolation and characterization of a marine-derived natural product, N⁶,N⁶-dimethyladenosine, that robustly inhibits AKT signaling in a variety of non-small cell lung cancer cell lines. Upon validation of the elucidated structure by comparison with a commercially available sample, experiments were initiated to understand the small molecule’s breadth of effect in a biological setting. One such experiment, a reverse phase protein array (RPPA) analysis of >50 kinases, indicated a specific cellular response to treatment. In all, leveraging the FUSION platform allowed for the rapid generation and validation of a biological mechanism of action hypothesis for an unknown natural product and permitted accelerated purification of the bioactive component from a chemically complex fraction. Full article

(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)

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Review

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809 KiB

Open AccessFeature PaperReview

Marine Sponge Natural Products with Anticancer Potential: An Updated Review

by Cinzia Calcabrini, Elena Catanzaro, Anupam Bishayee, Eleonora Turrini and Carmela Fimognari

Mar. Drugs 2017, 15(10), 310; https://doi.org/10.3390/md15100310 - 13 Oct 2017

Cited by 109 | Viewed by 13973

Abstract

Despite the huge investment into research and the significant effort and advances made in the search for new anticancer drugs in recent decades, cancer cure and treatment continue to be a formidable challenge. Many sources, including plants, animals, and minerals, have been explored [...] Read more.

Despite the huge investment into research and the significant effort and advances made in the search for new anticancer drugs in recent decades, cancer cure and treatment continue to be a formidable challenge. Many sources, including plants, animals, and minerals, have been explored in the oncological field because of the possibility of identifying novel molecular therapeutics. Marine sponges are a prolific source of secondary metabolites, a number of which showed intriguing tumor chemopreventive and chemotherapeutic properties. Recently, Food and Drug Administration-approved drugs derived from marine sponges have been shown to reduce metastatic breast cancer, malignant lymphoma, and Hodgkin’s disease. The chemopreventive and potential anticancer activity of marine sponge-derived compounds could be explained by multiple cellular and molecular mechanisms, including DNA protection, cell-cycle modulation, apoptosis, and anti-inflammatory activities as well as their ability to chemosensitize cancer cells to traditional antiblastic chemotherapy. The present article aims to depict the multiple mechanisms involved in the chemopreventive and therapeutic effects of marine sponges and critically explore the limitations and challenges associated with the development of marine sponge-based anticancer strategy. Full article

(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)

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1134 KiB

Open AccessFeature PaperReview

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates

by David J. Newman and Gordon M. Cragg

Mar. Drugs 2017, 15(4), 99; https://doi.org/10.3390/md15040099 - 29 Mar 2017

Cited by 60 | Viewed by 8563

Abstract

In this review, we have attempted to describe all of the antibody–drug conjugates using a marine-derived compound as the “warhead”, that are currently in clinical trials as listed in the current version of the NIH clinical trials database (clinicaltrials.gov). In searching this database, [...] Read more.

In this review, we have attempted to describe all of the antibody–drug conjugates using a marine-derived compound as the “warhead”, that are currently in clinical trials as listed in the current version of the NIH clinical trials database (clinicaltrials.gov). In searching this database, we used the beta-test version currently available, as it permitted more specific search parameters, since the regular version did not always find trials that had been completed in the past with some agents. We also added small discussion sections on candidates that are still at the preclinical stage, including a derivative of diazonamide that has an unusual interaction with tubulin (DZ-23840), which may also be a potential warhead in the future. Full article

(This article belongs to the Special Issue Marine Drugs as Antitumour Agents 2017)

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