Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation,Journal of Natural Products

当前位置： X-MOL 学术 › J. Nat. Prod. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation
Journal of Natural Products ( IF 3.3 ) Pub Date : 2018-03-14 00:00:00 , DOI: 10.1021/acs.jnatprod.7b00918
E. M. Kithsiri Wijeratne ₁ , Maria C. F. Oliveira _{1,

2} , Jair Mafezoli _{1,

2} , Ya-Ming Xu ₁ , Sandro Minguzzi _{1,

3} , Pedro H. J. Batista ₂ , Otília D. L. Pessoa ₂ , Luke Whitesell ₄ , A. A. Leslie Gunatilaka ₁

Affiliation

Withanolides constitute a valuable class of bioactive natural products because some members of the class are known to exhibit cytotoxic activity and also induce a cytoprotective heat-shock response. In order to understand the relationship between their structures and these dual bioactivities of the withanolide scaffold, we obtained 25 analogues of withaferin A (WA) and withanolide D (WD) including 17 new compounds by semisynthesis involving chemical and microbial transformations. Hitherto unknown 16β-hydroxy analogues of WA and WD were prepared by their reaction with triphenylphosphine/iodine, providing unexpected 5β-hydroxy-6α-iodo analogues (iodohydrins) followed by microbial biotransformation with Cunninghamella echinulata and base-catalyzed cyclization of the resulting 16β-hydroxy iodohydrins. Evaluation of these 25 withanolide analogues for their cytotoxicity and heat-shock-inducing activity (HSA) confirmed the known structure–activity relationships for WA-type withanolides and revealed that WD analogues were less active in both assays compared to their corresponding WA analogues. The 5β,6β-epoxide moiety of withanolides contributed to their cytotoxicity but not HSA. Introduction of a 16β-OAc group to 4,27-di-O-acetyl-WA enhanced cytotoxicity and decreased HSA, whereas introduction of the same group to 4-O-acetyl-WD decreased both activities.

中文翻译：

具有双重热休克诱导和细胞毒活性的Withaferin A和Withanolide D类似物：半合成和生物学评估

Withanolides构成一类有价值的生物活性天然产物，因为已知该类化合物的某些成员表现出细胞毒活性，并且还诱导细胞保护性热休克反应。为了了解其结构与withanolide支架的双重生物活性之间的关系，我们通过涉及化学和微生物转化的半合成获得了25种withaferin A（WA）和withanolide D（WD）的类似物，包括17种新化合物。通过与三苯基膦/碘反应制备了迄今未知的WA和WD16β-羟基类似物，提供了出乎意料的5β-羟基-6α-碘类似物（碘代醇），然后用棘枝棘孢菌进行了微生物生物转化。和碱催化环化所得的16β-羟基碘醇。对这25种withanolide类似物的细胞毒性和热激诱导活性（HSA）进行评估，证实了WA型withanolides具有已知的结构-活性关系，并揭示了在两种测定法中WD类似物与其相应的WA类似物相比活性较低。醇化物的5β，6β-环氧部分有助于其细胞毒性，但对HSA无贡献。一个16β-OAC基团的引入到4,27二ø -乙酰基WA增强的细胞毒性和降低的HSA，而导入同一组的至4- ö乙酰基WD降低两种活性。

更新日期：2018-03-14

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11