Fong-Kai Lee, Nathaniel Jia-Yoong Chan, Premanand Krishnan, Dayang Sharyati Datu Abdul Salam, Xavier Wezen Chee, Azira Muhamad, Yun-Yee Low, Kang-Nee Ting and Kuan-Hon Lim*,
{"title":"作为血管舒张剂的 Schwarzinicine A 类似物的制备和初步结构-活性关系研究。","authors":"Fong-Kai Lee, Nathaniel Jia-Yoong Chan, Premanand Krishnan, Dayang Sharyati Datu Abdul Salam, Xavier Wezen Chee, Azira Muhamad, Yun-Yee Low, Kang-Nee Ting and Kuan-Hon Lim*, ","doi":"10.1021/acs.jnatprod.3c00707","DOIUrl":null,"url":null,"abstract":"<p >Schwarzinicines A–D, a series of alkaloids recently discovered from <i>Ficus schwarzii</i>, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (<b>1</b>) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (<i>E</i><sub>max</sub>) and potency (EC<sub>50</sub>) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to <b>1</b>. Molecular dynamics simulation of a tetrameric <b>44</b>-bound transient receptor potential canonical-6 (TRPC6) protein indicated that <b>44</b> could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Preparation and Preliminary Structure–Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents\",\"authors\":\"Fong-Kai Lee, Nathaniel Jia-Yoong Chan, Premanand Krishnan, Dayang Sharyati Datu Abdul Salam, Xavier Wezen Chee, Azira Muhamad, Yun-Yee Low, Kang-Nee Ting and Kuan-Hon Lim*, \",\"doi\":\"10.1021/acs.jnatprod.3c00707\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Schwarzinicines A–D, a series of alkaloids recently discovered from <i>Ficus schwarzii</i>, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (<b>1</b>) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (<i>E</i><sub>max</sub>) and potency (EC<sub>50</sub>) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to <b>1</b>. Molecular dynamics simulation of a tetrameric <b>44</b>-bound transient receptor potential canonical-6 (TRPC6) protein indicated that <b>44</b> could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs.</p>\",\"PeriodicalId\":47,\"journal\":{\"name\":\"Journal of Natural Products \",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-03-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Natural Products \",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jnatprod.3c00707\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Natural Products ","FirstCategoryId":"99","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jnatprod.3c00707","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Preparation and Preliminary Structure–Activity Relationship Studies of Schwarzinicine A Analogs as Vasorelaxant Agents
Schwarzinicines A–D, a series of alkaloids recently discovered from Ficus schwarzii, exhibit pronounced vasorelaxant activity in rat isolated aorta. Building on this finding, a concise synthesis of schwarzinicines A and B has been reported, allowing further investigations into their biological properties. Herein, a preliminary exploration of the chemical space surrounding the structure of schwarzinicine A (1) was carried out aiming to identify structural features that are essential for vasorelaxant activity. A total of 57 analogs were synthesized and tested for vasorelaxant activity in rat isolated aorta. Both efficacy (Emax) and potency (EC50) of these analogs were compared. In addition to identifying structural features that are required for activity or associated with potency enhancement effect, four analogs showed significant potency improvements of up to 40.2-fold when compared to 1. Molecular dynamics simulation of a tetrameric 44-bound transient receptor potential canonical-6 (TRPC6) protein indicated that 44 could potentially form important interactions with the residues Glu509, Asp530, Lys748, Arg758, and Tyr521. These results may serve as a foundation for guiding further structural optimization of the schwarzinicine A scaffold, aiming to discover even more potent analogs.
期刊介绍:
The Journal of Natural Products invites and publishes papers that make substantial and scholarly contributions to the area of natural products research. Contributions may relate to the chemistry and/or biochemistry of naturally occurring compounds or the biology of living systems from which they are obtained.
Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.
When new compounds are reported, manuscripts describing their biological activity are much preferred.
Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.