Kevin Seipp, Claudia Kammler, Nils Ole Rossdam, Paul Eckhardt, Anna Maria Kiefer, Gerhard Erkel and Till Opatz*,
{"title":"抗炎大内酯 13-羟基-14-脱氧氧杂环十二烷二酮的全合成、结构重定和生物学评价。","authors":"Kevin Seipp, Claudia Kammler, Nils Ole Rossdam, Paul Eckhardt, Anna Maria Kiefer, Gerhard Erkel and Till Opatz*, ","doi":"10.1021/acs.jnatprod.4c00082","DOIUrl":null,"url":null,"abstract":"<p >Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two <i>threo</i>-derivatives, and two <i>Z</i>-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13<i>R</i>,14<i>S</i>,15<i>R</i>)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV–vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced <i>E</i>/<i>Z</i> double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC<sub>50</sub> values in biological assays addressing the inhibition of cellular inflammatory responses.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Total Synthesis, Structure Reassignment, and Biological Evaluation of the Anti-Inflammatory Macrolactone 13-Hydroxy-14-deoxyoxacyclododecindione\",\"authors\":\"Kevin Seipp, Claudia Kammler, Nils Ole Rossdam, Paul Eckhardt, Anna Maria Kiefer, Gerhard Erkel and Till Opatz*, \",\"doi\":\"10.1021/acs.jnatprod.4c00082\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two <i>threo</i>-derivatives, and two <i>Z</i>-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13<i>R</i>,14<i>S</i>,15<i>R</i>)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV–vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced <i>E</i>/<i>Z</i> double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC<sub>50</sub> values in biological assays addressing the inhibition of cellular inflammatory responses.</p>\",\"PeriodicalId\":47,\"journal\":{\"name\":\"Journal of Natural Products \",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-03-31\",\"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.4c00082\",\"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.4c00082","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
本文首次报道了天然13-羟基-14-脱氧氧杂环十二烷二酮的全合成以及对拟议构型的修订。这种天然产物最初发现于2018年,属于氧杂环十二烷二酮家族,以其显著的抗炎和抗纤维化活性而闻名。合成路线涉及酯化/Friedel-Crafts-酰化方法,并使用了各种三醇片段。它可以制备出不同的立体异构体,包括(修正的)天然产物、两种三醇衍生物以及内环 C═C 双键的两种 Z 异构体。此外,C-13 立体中心的后期反转可将最初提出的结构转化为修正后的天然产物。有了这组完整的化合物和之前制备的 (13R,14S,15R) 异构体,我们对它们的结构特性和生物活性有了更深入的了解。利用光谱学(核磁共振、红外光谱、紫外-可见光谱)和 X 射线晶体学对最终的大内酯进行了详细分析,从而获得了新的认识,例如光学旋转对阐明其构型的重要意义以及光诱导的 E/Z 双键光异构化。在抑制细胞炎症反应的生物学实验中,这些化合物的 IC50 值非常低,这凸显了它们的药理潜力。
Total Synthesis, Structure Reassignment, and Biological Evaluation of the Anti-Inflammatory Macrolactone 13-Hydroxy-14-deoxyoxacyclododecindione
Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two threo-derivatives, and two Z-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13R,14S,15R)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV–vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced E/Z double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC50 values in biological assays addressing the inhibition of cellular inflammatory responses.
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.