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Marine Drugs
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Synthetic Studies of Marine Bioactive Natural Products and Analogs to...
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Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads

A special issue of Marine Drugs (ISSN 1660-3397). This special issue belongs to the section "Synthesis and Medicinal Chemistry of Marine Natural Products".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 6021

Special Issue Editor

Prof. Dr. Naoyuki Kotoku

E-Mail Website
Guest Editor
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga, 525-8577, Japan
Interests: marine natural products; synthesis; molecular targeted anti-cancer drugs

Special Issue Information

Dear Colleagues,

Marine natural products are considered promising sources of drug candidates, especially in the field of anticancer drugs or antibiotics. However, the scarce supply of compounds from natural sources often limits further drug development. On the other hand, efficient total synthesis of marine natural products and their derivatives can overcome this drawback. In addition, the synthesis of truncated analogs based on structure–activity relationship (SAR) studies would facilitate the discovery of more accessible drug lead compounds with improved bioactive specificity or ADMET profiles.

Therefore, the Special Issue will focus on the synthetic studies of bioactive marine natural products and their derivatives. Submissions on the development of truncated analogs leading to novel drug leads are also welcome.

Prof. Dr. Naoyuki Kotoku
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 products
  • total synthesis
  • synthetic derivatives
  • truncated analogs
  • structure–activity relationship

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Published Papers (6 papers)

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Research

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15 pages, 2375 KiB  
Article
Synthesis and Evaluation of Antitumor and Anti-Angiogenesis Activity of Pyrone- or Pyridone-Embedded Analogs of Cortistatin A
by Yuri Fujimoto, Kanako Mizuno, Yuta Nakamura, Masayoshi Arai and Naoyuki Kotoku
Mar. Drugs 2025, 23(4), 179; https://doi.org/10.3390/md23040179 - 20 Apr 2025
Viewed by 319
Abstract
Simplified analogs of cortistatin A were synthesized and biologically evaluated to develop novel antitumor substances that target angiogenesis. To analyze the effect of substituents at positions corresponding to C-2 and/or C-4 of the A-ring, various pyrone- or pyridone-embedded analogs were designed and synthesized. [...] Read more.
Simplified analogs of cortistatin A were synthesized and biologically evaluated to develop novel antitumor substances that target angiogenesis. To analyze the effect of substituents at positions corresponding to C-2 and/or C-4 of the A-ring, various pyrone- or pyridone-embedded analogs were designed and synthesized. Among the prepared analogs, the pyridone analog 19 bearing a methyl group at C-2 and a hydroxyl group at C-4 showed potent and selective growth inhibitory activity against human umbilical vein endothelial cells (HUVECs, IC50 = 0.001 µM, selective index over that against human epidermoid carcinoma KB3-1 cells = 6400), exceeding those of natural products. The analog 19 of oral administration exhibited excellent in vivo antitumor activity in mice subcutaneously inoculated with sarcoma S180 cells. Full article
(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)
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18 pages, 1948 KiB  
Article
Synthesis and Biological Activity of Glycosyl Thiazolyl Disulfides Based on Thiacarpine, an Analogue of the Cytotoxic Alkaloid Polycarpine from the Ascidian Polycarpa aurata
by Dmitry N. Pelageev, Yuri E. Sabutski, Svetlana M. Kovach, Nadezhda N. Balaneva, Ekaterina S. Menchinskaya, Ekaterina A. Chingizova, Anna L. Burylova and Victor Ph. Anufriev
Mar. Drugs 2025, 23(3), 117; https://doi.org/10.3390/md23030117 - 9 Mar 2025
Viewed by 859
Abstract
Polycarpine, a diimidazolyl disulfan alkaloid isolated from the ascidian Polycarpa aurata, showed high cytotoxic activity in vitro. However, in vivo experiments have shown that polycarpine has a high acute toxicity. At the same time, its synthetic thiazolyl analog, thiacarpine, showed less acute [...] Read more.
Polycarpine, a diimidazolyl disulfan alkaloid isolated from the ascidian Polycarpa aurata, showed high cytotoxic activity in vitro. However, in vivo experiments have shown that polycarpine has a high acute toxicity. At the same time, its synthetic thiazolyl analog, thiacarpine, showed less acute toxicity and had a greater therapeutic index, which makes its derivatives promising for further drug development. We assume that due to the presence of a disulfide bond in the molecules of polycarpine and thiacarpine and the possibility of its reduction in a living cell, the mercapto derivatives formed are responsible for the high activity of the original compounds. Based on this assumption, and to increase the selectivity of action, glycosyl disulfide conjugates of thiacarpine derivatives with thioglucose and thioxylose were synthesized and screened for their cytotoxic and antimicrobial activities. The target compounds did not show hemolytic activity at concentrations of up to 25 μM. Some of them exhibited moderate cytotoxic activity, blocked colony growth and migration of HeLa tumor cells, high antimicrobial activity, and inhibited biofilm formation comparable to or higher than that of a standard antibiotic (gentamicin) and antimycotic (nitrofungin). Full article
(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)
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17 pages, 1477 KiB  
Article
Total Synthesis of the Marine Cyclic Depsipeptide Lagunamide D
by Huiru Nan, Xiong-En Long, Jianfei He, Hailiang Xing, Min-Jing Cheng, Jin-Bao Peng, Tao Ye, Jia-Lei Yan and Junyang Liu
Mar. Drugs 2025, 23(3), 99; https://doi.org/10.3390/md23030099 - 24 Feb 2025
Viewed by 632
Abstract
Lagunamide D is a structurally distinct 26-membered cytotoxic cyclic depsipeptide, originally isolated from a marine cyanobacterium. It exhibits potent antiproliferative activity in the low nanomolar range against A549 human lung adenocarcinoma cells and HCT116 colon cancer cells. A significant challenge associated with lagunamide [...] Read more.
Lagunamide D is a structurally distinct 26-membered cytotoxic cyclic depsipeptide, originally isolated from a marine cyanobacterium. It exhibits potent antiproliferative activity in the low nanomolar range against A549 human lung adenocarcinoma cells and HCT116 colon cancer cells. A significant challenge associated with lagunamide D is its propensity for intramolecular acyl migration, which leads to the formation of a contracted 24-membered analog, lagunamide D′. This structural rearrangement complicates its isolation, characterization, and synthesis. In this study, the total synthesis of lagunamide D was achieved in a 14-step longest linear sequence, starting from the known intermediate 17, with an overall yield of 4.6%. The synthetic strategy involved several key transformations, including Ghosh’s TiCl4-promoted anti-aldol reaction, Corey–Bakshi–Shibata reduction (CBS reduction), cross-metathesis, Pinnick oxidation, and Yamaguchi esterification. Furthermore, this synthetic effort unambiguously confirmed the stereochemistry of the natural product. Full article
(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)
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14 pages, 2818 KiB  
Article
Structure-Activity Relationship Study of Majusculamide D: Overcoming Metabolic Instability and Severe Toxicity with a Fluoro Analogue
by Xiuhe Zhao, Xiaonan Xi, Mingxiao Zhang, Mengxue Lv, Xiang Zhang, Yaxin Lu, Liang Wang and Yue Chen
Mar. Drugs 2024, 22(12), 537; https://doi.org/10.3390/md22120537 - 29 Nov 2024
Cited by 1 | Viewed by 1126
Abstract
Majusculamide D, isolated from the marine cyanobacterium Moorea producens, is an anticancer lipopentapeptide consisting of fatty acid, tripeptide, and pyrrolyl proline moieties. In this work, by utilizing a convergent synthetic approach, late-stage modification, and bioisostere strategy, 26 majusculamide D analogues were synthesized, [...] Read more.
Majusculamide D, isolated from the marine cyanobacterium Moorea producens, is an anticancer lipopentapeptide consisting of fatty acid, tripeptide, and pyrrolyl proline moieties. In this work, by utilizing a convergent synthetic approach, late-stage modification, and bioisostere strategy, 26 majusculamide D analogues were synthesized, and two (1i and 1j) demonstrated IC50 values < 1 nM against PANC-1 cancer cells. The results summarized a preliminary structure-activity relationship mainly at the C23, C4, C34, and C10 sites. A series of in vitro assays, including wound healing, transwell, clone formation, EdU, and western blot, confirmed that majusculamide D inhibited the migration, invasion, and proliferation of pancreatic cancer cells. The optimized fluorinated analogue 1n demonstrated a notable enhancement in stability during the mouse plasma assay (>50% left after 24 h), exhibited tumor-suppressive effects (51.5% at a dosage of 5 mg/kg), and successfully mitigated the severe toxicity (no mouse dead) observed in the group treated with majusculamide D (3 mice dead) in a xenografted mouse model. Full article
(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)
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13 pages, 4888 KiB  
Article
Design, Synthesis, and Evaluation of Novel Thiazole-Containing Algicides Inspired by Bacillamide A
by Xiaoxue Li, Huili Li, Lei Shi, Zuguang Yin, Yuguo Du, Hongxia Zhang, Xin Wang, Xinxin Wang, Kexin Xu, Weili Wang, Ronglian Xing and Yi Liu
Mar. Drugs 2024, 22(11), 494; https://doi.org/10.3390/md22110494 - 1 Nov 2024
Viewed by 1469
Abstract
The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency [...] Read more.
The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency and large dose requirements of bacillamide A limit its further application. In this paper, 17 thiazole-containing bacillamide derivatives (BDs) were designed and synthesized in three linear steps as potential algicides. Eight compounds (6a, 6c, 6j, 7b, 7c, 7d, 7e, and 7g) displayed potent inhibitory effects against Prorocentrum minimum, Skeletonema costatum, and Alexandrium pacificum, and they had similar or better activity than the positive control (CuSO4) and bacillamide A. Compound 6a exhibited the most potent algicidal activity against S. costatum (half-maximal effective concentration [EC50] = 0.11 μg/mL), being 23-fold more potent than bacillamide A, 28-fold more potent than CuSO4, and 39-fold more potent than Diuron. Compound 6j exhibited significant algicidal activity against the toxic dinoflagellates P. minimum (EC50 = 1.0 μg/mL) and A. pacificum (EC50 = 0.47 μg/mL), being 3–5-fold more potent than natural bacillamide A, Diuron, and CuSO4. Micrographs and SEM images revealed that 6j induced cell wall rupture and cellular content leakage. Biochemical and physiological studies indicated that 6j might partially disrupt the antioxidant and photosynthetic systems in algal cells, resulting in morphological changes, cell wall rupture, and inclusion leakage. Our work suggests that 6j has a distinct mode of action from CuSO4 and provides a promising candidate for the development of new algicides, worthy of further investigation. Full article
(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)
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Review

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39 pages, 14151 KiB  
Review
Syntheses of Marine Natural Products via Matteson Homologations and Related Processes
by Uli Kazmaier
Mar. Drugs 2025, 23(1), 20; https://doi.org/10.3390/md23010020 - 2 Jan 2025
Cited by 1 | Viewed by 1125
Abstract
Matteson homologation, a successive extension of chiral boronic esters, is perfectly suited for the synthesis of complex molecular structures containing several stereogenic centers. The “classical version” allows the introduction of various functional groups in a 1,2-anti-configuration. The absolute configuration is determined [...] Read more.
Matteson homologation, a successive extension of chiral boronic esters, is perfectly suited for the synthesis of complex molecular structures containing several stereogenic centers. The “classical version” allows the introduction of various functional groups in a 1,2-anti-configuration. The absolute configuration is determined by the choice of the chiral auxiliary, which can be used to introduce several stereogenic centers. In contrast, in Aggarwal’s lithiation-borylation strategy, new chiral auxiliary reagents must be used in each reaction step, which on the other hand allows the individual insertion of the desired stereogenic centers. Both methods have their individual advantages and disadvantages and are well suited for the synthesis of marine natural products. Full article
(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)
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