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Marine Drugs
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Chemical Modification and Structural Elucidation of Marine Natural Products
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Chemical Modification and Structural Elucidation of Marine Natural Products

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: closed (28 February 2023) | Viewed by 16769

Special Issue Editor

Prof. Dr. Yoshihide Usami

E-Mail Website
Guest Editor
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, Japan
Interests: marine natural product; total synthesis; structural determination; bioactive; small molecule; azole
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over half a century ago, scientists in the field of marine natural product chemistry began to focus on discovering new drug seeds from the marine environment different from traditional terrestrial plants, animals, and microorganisms. To date, many scientists all over the world have worked in this area for new drug development. However, securing quantities of bioactive material is a significant disadvantage for drug development with marine natural products. Massive collection of marine animals and plants should be strictly prohibited from the position of marine environmental maintenance. One resolution of this problem is the culturing of marine animals or plants and fermentation of marine organisms producing bioactive compounds. Another is chemical modification based on bioactive marine natural products to obtain more active molecules than mother compounds. A well-known successful story is the development of an anticancer drug Eribulin by Eizai Inc. and Professor Kishi in 2010, starting from the discovery of halichondrin B from a sponge in 1986 by Japanese chemists Hirata and Uemura.

This Special Issue of Marine Drugs entitled “Chemical Modification and Structural Elucidation of Marine Natural Products” aims to collect excellent original research articles and reviews focused on precious efforts of outstanding scientists struggling with chemical modification for development in this research field. In addition, papers on chemical-reaction-aided structural elucidation of newly discovered marine natural products are encouraged. The Editorial Office and I welcome your contribution to this Special Issue and hope this Special Issue might lead to new drug discoveries.

Prof. Dr. Yoshihide Usami
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
  • bioactive
  • total synthesis
  • chemical modification
  • semi-synthesis
  • structural determination
  • active molecules

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Published Papers (7 papers)

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Research

14 pages, 3459 KiB  
Article
Design, Synthesis, Antifungal Activity, and Molecular Docking of Streptochlorin Derivatives Containing the Nitrile Group
by Jing-Rui Liu, Ya Gao, Bing Jin, Dale Guo, Fang Deng, Qiang Bian, Hai-Feng Zhang, Xin-Ya Han, Abdallah S. Ali, Ming-Zhi Zhang, Wei-Hua Zhang and Yu-Cheng Gu
Mar. Drugs 2023, 21(2), 103; https://doi.org/10.3390/md21020103 - 31 Jan 2023
Cited by 3 | Viewed by 2674
Abstract
Based on the structures of natural products streptochlorin and pimprinine derived from marine or soil microorganisms, a series of streptochlorin derivatives containing the nitrile group were designed and synthesized through acylation and oxidative annulation. Evaluation for antifungal activity showed that compound 3a could [...] Read more.
Based on the structures of natural products streptochlorin and pimprinine derived from marine or soil microorganisms, a series of streptochlorin derivatives containing the nitrile group were designed and synthesized through acylation and oxidative annulation. Evaluation for antifungal activity showed that compound 3a could be regarded as the most promising candidate—it demonstrated over 85% growth inhibition against Botrytis cinerea, Gibberella zeae, and Colletotrichum lagenarium, as well as a broad antifungal spectrum in primary screening at the concentration of 50 μg/mL. The SAR study revealed that non-substituent or alkyl substituent at the 2-position of oxazole ring were favorable for antifungal activity, while aryl and monosubstituted aryl were detrimental to activity. Molecular docking models indicated that 3a formed hydrogen bonds and hydrophobic interactions with Leucyl-tRNA Synthetase, offering a perspective for the possible mechanism of action for antifungal activity of the target compounds. Full article
(This article belongs to the Special Issue Chemical Modification and Structural Elucidation of Marine Natural Products)
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13 pages, 6890 KiB  
Article
Discovery of Novel Pimprinine and Streptochlorin Derivatives as Potential Antifungal Agents
by Jing-Rui Liu, Jia-Mu Liu, Ya Gao, Zhan Shi, Ke-Rui Nie, Dale Guo, Fang Deng, Hai-Feng Zhang, Abdallah S. Ali, Ming-Zhi Zhang, Wei-Hua Zhang and Yu-Cheng Gu
Mar. Drugs 2022, 20(12), 740; https://doi.org/10.3390/md20120740 - 25 Nov 2022
Cited by 4 | Viewed by 2696
Abstract
Pimprinine and streptochlorin are indole alkaloids derived from marine or soil microorganisms. In our previous study, they were promising lead compounds due to their potent bioactivity in preventing many phytopathogens, but further structural modifications are required to improve their antifungal activity. In this [...] Read more.
Pimprinine and streptochlorin are indole alkaloids derived from marine or soil microorganisms. In our previous study, they were promising lead compounds due to their potent bioactivity in preventing many phytopathogens, but further structural modifications are required to improve their antifungal activity. In this study, pimprinine and streptochlorin were used as parent structures with the combination strategy of their structural features. Three series of target compounds were designed and synthesized. Subsequent evaluation for antifungal activity against six common phytopathogenic fungi showed that some of thee compounds possessed excellent effects, and this is highlighted by compounds 4a and 5a, displaying 99.9% growth inhibition against Gibberella zeae and Alternaria Leaf Spot under 50 μg/mL, respectively. EC50 values indicated that compounds 4a, 5a, 8c, and 8d were even more active than Azoxystrobin and Boscalid. SAR analysis revealed the relationship between 5-(3′-indolyl)oxazole scaffold and antifungal activity, which provides useful insight into the development of new target molecules. Molecular docking models indicate that compound 4a binds with leucyl-tRNA synthetase in a similar mode as AN2690, offering a perspective on the mode of action for the study of its antifungal activity. These results suggest that compounds 4a and 5a could be regarded as novel and promising antifungal agents against phytopathogens due to their valuable potency. Full article
(This article belongs to the Special Issue Chemical Modification and Structural Elucidation of Marine Natural Products)
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14 pages, 2065 KiB  
Article
Regioselective Synthesis of 6-O-Acetyl Dieckol and Its Selective Cytotoxicity against Non-Small-Cell Lung Cancer Cells
by Hyeon-Cheol Shin, Yongkyun Kim, Jaeyeong Choi, Hyun Bae Kang, Seung-Yun Han, Kwangyong Park and Hye Jeong Hwang
Mar. Drugs 2022, 20(11), 683; https://doi.org/10.3390/md20110683 - 29 Oct 2022
Cited by 1 | Viewed by 1919
Abstract
Dieckol, a phlorotannin from Ecklonia cava, has shown potential for use as an anticancer agent that selectively kills cancer cells. However, it is necessary to amplify its potency without damaging its inherent safety in order to develop it as a competitive chemotherapeutic. [...] Read more.
Dieckol, a phlorotannin from Ecklonia cava, has shown potential for use as an anticancer agent that selectively kills cancer cells. However, it is necessary to amplify its potency without damaging its inherent safety in order to develop it as a competitive chemotherapeutic. Here, we explored the controlled O-acylations of dieckol. Acyl groups could be consistently introduced to the 6-O position of dieckol with a high regioselectivity, which was confirmed by NOESY, HMBC and HSQC spectroscopies. In cytotoxicity studies on the newly synthesized 6-O-acetyl, 6-O-benzoyl dieckols and previously synthesized 6-O-alkyl dieckols against A549 vs. normal cells, all of the derivatives showed low cytotoxicity in normal cells with an IC50 of 481–719 μM, and highly structure-dependent cytotoxicity in A549 cells with an IC50 of 7.02 (acetyl)−842.26 (benzyl) μM. The selectivity index also showed a large structure dependency in the range of 0.67 (benzyl)–68.58 (acetyl). An analysis of the structure–activity relationship indicated that the activity was dramatically reduced in the presence of a benzene ring and was highly increased in the presence of small polar substituents. Conclusions: Controlled mono-O-modifications of dieckol could be a powerful tool to enhance the anticancer activity of dieckol, thus contributing to the development strategy for dieckol-based chemotherapeutics. Full article
(This article belongs to the Special Issue Chemical Modification and Structural Elucidation of Marine Natural Products)
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28 pages, 2127 KiB  
Article
Total Synthesis and Biological Evaluation of Modified Ilamycin Derivatives
by Jennifer Greve, Axel Mogk and Uli Kazmaier
Mar. Drugs 2022, 20(10), 632; https://doi.org/10.3390/md20100632 - 3 Oct 2022
Cited by 14 | Viewed by 2412
Abstract
Ilamycins/rufomycins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis. The cyclic peptides target the AAA+ protein ClpC1 that, together with the peptidases ClpP1/ClpP2, [...] Read more.
Ilamycins/rufomycins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis. The cyclic peptides target the AAA+ protein ClpC1 that, together with the peptidases ClpP1/ClpP2, forms an essential ATP-driven protease. Derivatives of the ilamycins with a simplified tryptophane unit are synthesized in a straightforward manner. The ilamycin derivative 26 with a cyclic hemiaminal structure is active in the nM-range against several mycobacterial strains and shows no significant cytotoxicity. In contrast, derivative 27, with a glutamic acid at this position, is significantly less active, with MICs in the mid µM-range. Detailed investigations of the mode of action of 26 indicate that 26 deregulates ClpC1 activity and strongly enhances ClpC1-WT ATPase activity. The consequences of 26 on ClpC1 proteolytic activities were substrate-specific, suggesting dual effects of 26 on ClpC1-WT function. The positive effect relates to ClpC1-WT ATPase activation, and the negative to competition with substrates for binding to the ClpC1 NTD. Full article
(This article belongs to the Special Issue Chemical Modification and Structural Elucidation of Marine Natural Products)
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30 pages, 2722 KiB  
Article
Total Syntheses of the Proposed Structure of Iriomoteolide-1a, -1b and Synthesis of Three Derivatives for Structural Studies
by Arun K. Ghosh and Hao Yuan
Mar. Drugs 2022, 20(10), 587; https://doi.org/10.3390/md20100587 - 20 Sep 2022
Cited by 4 | Viewed by 1976
Abstract
Iriomoteolide-1a and iriomoteolide-1b are very potent cytotoxic agents, isolated from marine dinoflagellates. We carried out the enantioselective syntheses of the proposed structures of these natural products. However, our analysis of the NMR spectra of the synthetic iriomoteolide-1a and the natural products revealed that [...] Read more.
Iriomoteolide-1a and iriomoteolide-1b are very potent cytotoxic agents, isolated from marine dinoflagellates. We carried out the enantioselective syntheses of the proposed structures of these natural products. However, our analysis of the NMR spectra of the synthetic iriomoteolide-1a and the natural products revealed that the structures of iriomoteolide-1a and iriomoteolide-1b were assigned incorrectly. Based upon our detailed analysis of the spectral data of the synthetic iriomoteolide-1a and the natural products, we rationally designed three diastereomers of the proposed structure of 1 in an effort to assign the correct structures. The key steps of our syntheses of the proposed structures of iriomoteolides involved a highly diastereoselective ene reaction, a carbocupration that utilized a Gilman reagent, a Julia–Kocienski olefination to couple fragments, and Yamaguchi macrolactonization to form the target macrolactone. This synthetic route was then utilized to carry out syntheses of three diastereomers to the proposed structure of 1. These diastereomeric structures show close similarities to natural iriomoteolide-1a; however, there were differences in their spectral data. While natural iriomoteolides exhibited potent cytotoxicies, our preliminary biological evaluation of synthetic iriomoteolide-1a, iriomoteolide-1b, and all three synthetic derivatives did not show any appreciable cytotoxic properties. Full article
(This article belongs to the Special Issue Chemical Modification and Structural Elucidation of Marine Natural Products)
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14 pages, 4022 KiB  
Article
Synthesis of 6-Halo-Substituted Pericosine A and an Evaluation of Their Antitumor and Antiglycosidase Activities
by Yoshihide Usami, Yoshino Mizobuchi, Mai Ijuin, Takeshi Yamada, Mizuki Morita, Koji Mizuki, Hiroki Yoneyama and Shinya Harusawa
Mar. Drugs 2022, 20(7), 438; https://doi.org/10.3390/md20070438 - 30 Jun 2022
Cited by 1 | Viewed by 2003
Abstract
The enantiomers of 6-fluoro-, 6-bromo-, and 6-iodopericosine A were synthesized. An efficient synthesis of both enantiomers of pericoxide via 6-bromopericosine A was also developed. These 6-halo-substituted pericosine A derivatives were evaluated in terms of their antitumor activity against three types of tumor cells [...] Read more.
The enantiomers of 6-fluoro-, 6-bromo-, and 6-iodopericosine A were synthesized. An efficient synthesis of both enantiomers of pericoxide via 6-bromopericosine A was also developed. These 6-halo-substituted pericosine A derivatives were evaluated in terms of their antitumor activity against three types of tumor cells (p388, L1210, and HL-60) and glycosidase inhibitory activity. The bromo- and iodo-congeners exhibited moderate antitumor activity similar to pericosine A against the three types of tumor cell lines studied. The fluorinated compound was less active than the others, including pericosine A. In the antitumor assay, no significant difference in potency between the enantiomers was observed for any of the halogenated compounds. Meanwhile, the (−)-6-fluoro- and (−)-6-bromo-congeners inhibited α-glucosidase to a greater extent than those of their corresponding (+)-enantiomers, whereas (+)-iodopericosine A showed increased activity when compared to its (−)-enantiomer. Full article
(This article belongs to the Special Issue Chemical Modification and Structural Elucidation of Marine Natural Products)
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12 pages, 1664 KiB  
Article
Isolation and Structure Elucidation of New Cytotoxic Macrolides Halosmysins B and C from the Fungus Halosphaeriaceae sp. Associated with a Marine Alga
by Takeshi Yamada, Kanoko Yoshida, Takashi Kikuchi and Tomoya Hirano
Mar. Drugs 2022, 20(4), 226; https://doi.org/10.3390/md20040226 - 25 Mar 2022
Cited by 2 | Viewed by 2300
Abstract
Two new cytotoxic metabolites, halosmysins B and C, have been isolated from the fungus Halosphaeriaceae sp. OUPS-135D-4 separated from the marine alga Sargassum thunbergii. These chemical structures have been elucidated by 1D and 2D NMR, and HRFABMS spectral analyses. The new compounds had [...] Read more.
Two new cytotoxic metabolites, halosmysins B and C, have been isolated from the fungus Halosphaeriaceae sp. OUPS-135D-4 separated from the marine alga Sargassum thunbergii. These chemical structures have been elucidated by 1D and 2D NMR, and HRFABMS spectral analyses. The new compounds had the same 14-membered macrodiolide skeleton as halosmysin A, which was isolated from this fungal strain previously. As the unique structural feature, a diketopiperazine derivative and a sugar are conjugated to the 14-membered ring of halosmysins B and C, respectively. The absolute stereostructures of them were elucidated by the chemical derivatization such as a hydrolysis, the comparison with the known compounds (6R,11R,12R,14R)-colletodiol and halosmysin A, and a HPLC analysis of sugar. In addition, their cytotoxicities were assessed using murine P388 leukemia, human HL-60 leukemia, and murine L1210 leukemia cell lines. Halosmysin B was shown to be potent against all of them, with IC50 values ranging from 8.2 ± 1.8 to 20.5 ± 3.6 μM, though these values were slightly higher than those of halosmysin A. Full article
(This article belongs to the Special Issue Chemical Modification and Structural Elucidation of Marine Natural Products)
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