Bioactivity-Focused Syntheses of Marine Natural Products and Congeners

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (28 February 2014) | Viewed by 45648

Special Issue Editor


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Guest Editor
Biomedical Research Centre, Sheffield Hallam University, City Campus, Howard Street, Sheffield, S1 1WB, UK
Interests: the natural origins of therapeutic drugs: natural product scaffolds

Special Issue Information

Dear Colleagues,

Marine natural products provide biologically-privileged frameworks for the discovery and development of new therapeutic drugs and biochemical tools. These development processes are frequently supported by synthetic chemistry, including total synthesis, semi-synthesis and congener synthesis. The roles played by synthesis and semi-synthesis include: (1) providing access to adequate quantities of compounds when natural supply is limited; and (2) providing novel analogues for biological evaluation (i.e. develop structure-activity relationships). These efforts can lead to more efficacious compounds, or simplified analogues that retain the desirable biological activity. This Special Issue of Marine Drugs focuses on the use of synthesis to support the discovery and development of marine natural products and congeners as drugs and biochemical tool compounds.

You are cordially invited to submit original papers and review articles to “Bioactivity-Focused Syntheses of Marine Natural Products and Congeners”. Papers describing biological screening of libraries of synthetic or semi-synthetic marine natural product derivatives are encouraged. Manuscripts describing total syntheses, semi-syntheses and analogue syntheses are most welcome provided they include some details of biological evaluations.

Dr Malcolm W. B. McCulloch
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • marine natural product
  • total synthesis
  • semi-synthesis
  • analogue synthesis
  • structure-activity relationships
  • bioactive natural product derivatives
  • bioactivity profiling
  • screening of synthetic and semi-synthetic compound libraries

Published Papers (6 papers)

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Research

989 KiB  
Article
An Improved High Yield Total Synthesis and Cytotoxicity Study of the Marine Alkaloid Neoamphimedine: An ATP-Competitive Inhibitor of Topoisomerase IIα and Potent Anticancer Agent
by Linfeng Li, Adedoyin D. Abraham, Qiong Zhou, Hadi Ali, Jeremy V. O'Brien, Brayden D. Hamill, John J. Arcaroli, Wells A. Messersmith and Daniel V. LaBarbera
Mar. Drugs 2014, 12(9), 4833-4850; https://doi.org/10.3390/md12094833 - 19 Sep 2014
Cited by 10 | Viewed by 7334
Abstract
Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been [...] Read more.
Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC50 values) in all, with significant potency against colorectal cancer (lowest IC50 = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis. Full article
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Article
Investigation of Indolglyoxamide and Indolacetamide Analogues of Polyamines as Antimalarial and Antitrypanosomal Agents
by Jiayi Wang, Marcel Kaiser and Brent R. Copp
Mar. Drugs 2014, 12(6), 3138-3160; https://doi.org/10.3390/md12063138 - 28 May 2014
Cited by 19 | Viewed by 5963
Abstract
Pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine A and B (2 and 3) to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 μM, respectively) and Plasmodium falciparum (K1 dual drug resistant [...] Read more.
Pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine A and B (2 and 3) to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 μM, respectively) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 41 and 15 μM, respectively), but lacking in selectivity (L6 rat myoblast, IC50 24 μM and 25 μM, respectively). To expand the structure–activity relationship of this compound class towards both parasites, we have prepared and biologically tested a library of analogues that includes indoleglyoxyl and indoleacetic “capping acids”, and polyamines including spermine (PA3-4-3) and extended analogues PA3-8-3 and PA3-12-3. 7-Methoxy substituted indoleglyoxylamides were typically found to exhibit the most potent antimalarial activity (IC50 10–92 nM) but with varying degrees of selectivity versus the L6 rat myoblast cell line. A 6-methoxyindolglyoxylamide analogue was the most potent growth inhibitor of T. brucei (IC50 0.18 μM) identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 μM). There was no apparent correlation between antimalarial and anti-T. brucei activity in the series. In vivo evaluation of one analogue against Plasmodium berghei was undertaken, demonstrating a modest 20.9% reduction in parasitaemia. Full article
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Article
Synthesis and Anti-Tuberculosis Activity of the Marine Natural Product Caulerpin and Its Analogues
by Cristina I. Canché Chay, Rocío Gómez Cansino, Clara I. Espitia Pinzón, Rubén O. Torres-Ochoa and Roberto Martínez
Mar. Drugs 2014, 12(4), 1757-1772; https://doi.org/10.3390/md12041757 - 27 Mar 2014
Cited by 45 | Viewed by 8033
Abstract
Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b1g) were prepared using the same synthetic pathway with overall yields [...] Read more.
Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. The key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a4g). All bis-indole compounds synthesized were evaluated against the Mycobacterium tuberculosis strain H37Rv, and 1a was found to display excellent activity (IC50 0.24 µM). Full article
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Article
Synthesis and Evaluation of Some New Aza-B-homocholestane Derivatives as Anticancer Agents
by Yanmin Huang, Jianguo Cui, Sijing Chen, Qifu Lin, Huacan Song, Chunfang Gan, Bin Su and Aimin Zhou
Mar. Drugs 2014, 12(4), 1715-1731; https://doi.org/10.3390/md12041715 - 25 Mar 2014
Cited by 19 | Viewed by 6098
Abstract
Using analogues of some marine steroidal oximes as precursors, a series of aza-B-homocholestane derivatives possessing different substituted groups at the 3-position of the steroidal nucleus were synthesized. Their biological activity against cancer cell proliferation was determined with multiple cancer cell lines. [...] Read more.
Using analogues of some marine steroidal oximes as precursors, a series of aza-B-homocholestane derivatives possessing different substituted groups at the 3-position of the steroidal nucleus were synthesized. Their biological activity against cancer cell proliferation was determined with multiple cancer cell lines. Aza-B-homocholestane derivatives possessing 3-hydroxyl, 3-hydroximino and 3-thiosemicarbazone groups displayed remarkable cytotoxicity to cancer cells via apoptosis inducing mechanism. Compounds 5, 10, 12, 15 and 18 exhibited better potency to inhibit cancer cell proliferation. In addition, compound 15 was further evaluated with three dimensional (3D) multicellular spheroids assay to determine its potency against spheroid growth. The structure-activity relationship (SAR) generated in the studies is valuable for the design of novel chemotherapeutic agents. Full article
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Article
Antimicrobial Activity of the Marine Alkaloids, Clathrodin and Oroidin, and Their Synthetic Analogues
by Nace Zidar, Sofia Montalvão, Žiga Hodnik, Dorota A. Nawrot, Aleš Žula, Janez Ilaš, Danijel Kikelj, Päivi Tammela and Lucija Peterlin Mašič
Mar. Drugs 2014, 12(2), 940-963; https://doi.org/10.3390/md12020940 - 14 Feb 2014
Cited by 46 | Viewed by 9394
Abstract
Marine organisms produce secondary metabolites that may be valuable for the development of novel drug leads as such and can also provide structural scaffolds for the design and synthesis of novel bioactive compounds. The marine alkaloids, clathrodin and oroidin, which were originally isolated [...] Read more.
Marine organisms produce secondary metabolites that may be valuable for the development of novel drug leads as such and can also provide structural scaffolds for the design and synthesis of novel bioactive compounds. The marine alkaloids, clathrodin and oroidin, which were originally isolated from sponges of the genus, Agelas, were prepared and evaluated for their antimicrobial activity against three bacterial strains (Enterococcus faecalis, Staphylococcus aureus and Escherichia coli) and one fungal strain (Candida albicans), and oroidin was found to possess promising Gram-positive antibacterial activity. Using oroidin as a scaffold, 34 new analogues were designed, prepared and screened for their antimicrobial properties. Of these compounds, 12 exhibited >80% inhibition of the growth of at least one microorganism at a concentration of 50 µM. The most active derivative was found to be 4-phenyl-2-aminoimidazole 6h, which exhibited MIC90 (minimum inhibitory concentration) values of 12.5 µM against the Gram-positive bacteria and 50 µM against E. coli. The selectivity index between S. aureus and mammalian cells, which is important to consider in the evaluation of a compound’s potential as an antimicrobial lead, was found to be 2.9 for compound 6h. Full article
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Article
Synthesis and Neuroprotective Action of Xyloketal Derivatives in Parkinson’s Disease Models
by Shichang Li, Cunzhou Shen, Wenyuan Guo, Xuefei Zhang, Shixin Liu, Fengyin Liang, Zhongliang Xu, Zhong Pei, Huacan Song, Liqin Qiu, Yongcheng Lin and Jiyan Pang
Mar. Drugs 2013, 11(12), 5159-5189; https://doi.org/10.3390/md11125159 - 18 Dec 2013
Cited by 34 | Viewed by 8291
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (139) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1, 9, 23, 24, 36 and 39 strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans longevity-extending assay, compounds 1, 8, 15, 16 and 36 significantly extended the survival rates (p < 0.005 vs. dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson’s disease using the MPP+-induced C. elegans model, and compounds 1 and 8 exhibited the highest activities (p < 0.005 vs. MPP+). In the MPP+-induced C57BL/6 mouse PD model, 40 mg/kg of 1 and 8 protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p < 0.001 vs. MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD. Full article
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