Rajat Ghosh, Sima Biswas, Angshuman Bagchi, Shital K Chattopadhyay
{"title":"Synthesis and Evaluation of 9-<i>epi</i>-Koshidacin B as Selective Inhibitor of Histone Deacetylase 1.","authors":"Rajat Ghosh, Sima Biswas, Angshuman Bagchi, Shital K Chattopadhyay","doi":"10.1021/acs.jnatprod.4c00913","DOIUrl":null,"url":null,"abstract":"<p><p>A concise synthetic route to an epimer of the recently isolated biologically active cyclic tetrapeptide koshidacin B has been developed, which featured a late-stage functionalization of a macrocyclic scaffold through a cross metathesis reaction. The synthetic 9-<i>epi</i>-koshidacin B showed marginal differences in spectroscopic behavior with that of the natural product but exhibited conformational preferences similar to those reported for analogous substrate chlamydocin. Moreover, it exhibited a useful level of selective inhibition of biologically relevant enzyme histone deacetylase 1 with an IC<sub>50</sub> value of 0.145 μM over two other isoforms. Docking studies indicate that the natural product as well as its 9-epimer binds very similarly to the active site of HDAC1 indicating little influence of the configuration of the C9-stereocenter.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2024-12-10","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://doi.org/10.1021/acs.jnatprod.4c00913","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
我们开发出了一条合成最近分离出的具有生物活性的环状四肽柯西达辛 B 的表聚体的简明路线，其特点是通过交叉偏合成反应对一个大环支架进行后期官能化。合成的 9-epi-koshidacin B 在光谱行为上与天然产物略有不同，但在构象偏好上与已报道的类似底物 chlamydocin 相似。此外，它对生物相关酶组蛋白去乙酰化酶 1 具有有效的选择性抑制作用，其 IC50 值为 0.145 μM，高于其他两种同工酶。对接研究表明，该天然产物及其 9-表二聚体与 HDAC1 的活性位点结合非常相似，这表明 C9-stereocenter 的构型对其影响很小。
Synthesis and Evaluation of 9-epi-Koshidacin B as Selective Inhibitor of Histone Deacetylase 1.
A concise synthetic route to an epimer of the recently isolated biologically active cyclic tetrapeptide koshidacin B has been developed, which featured a late-stage functionalization of a macrocyclic scaffold through a cross metathesis reaction. The synthetic 9-epi-koshidacin B showed marginal differences in spectroscopic behavior with that of the natural product but exhibited conformational preferences similar to those reported for analogous substrate chlamydocin. Moreover, it exhibited a useful level of selective inhibition of biologically relevant enzyme histone deacetylase 1 with an IC50 value of 0.145 μM over two other isoforms. Docking studies indicate that the natural product as well as its 9-epimer binds very similarly to the active site of HDAC1 indicating little influence of the configuration of the C9-stereocenter.
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.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
