The Semisynthesis of 27-Deoxywithaferin A and 4-epi-5,6-Deoxywithaferin A from Withaferin A as Potential Antitumor Agents.

IF 3.6 2区生物学 Q2 CHEMISTRY, MEDICINAL

Journal of Natural Products Pub Date : 2025-09-05 DOI:10.1021/acs.jnatprod.5c00771

Yingfei Wang, Mingyue Lu, Yin Li, Xianxian Huang, Zhiling Liang, Yiheng Zhao, Hong Huang, Tingzhuang Yi, Di Su, Zhiming Yan

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引用次数: 0

Abstract

We describe two concise, three-step routes for the individual synthesis of 27-deoxywithaferin A (2) and 4-epi-5,6-deoxywithaferin A (4) from withaferin A (1). The protection strategy for the double bond of enone with thiophenol and the conjugate reduction of the epoxy group are important in generating these products, with an overall yield of 40%. The absolute configuration of 4-epi-5,6-deoxywithaferin A (4) has been confirmed by X-ray crystallography. 27-Deoxywithaferin A (2) exhibited a 400-fold higher potency than cisplatin against MCF-7 cells (IC₅₀ = 0.02 μM), while 4-epi-5,6-deoxywithaferin A (4) displayed variable IC₅₀ values (1.73-4.27 μM). Both compounds dose-dependently suppressed proliferation and induced apoptosis in MCF-7 cells, with 4-epi-5,6-deoxywithaferin A (4) demonstrating superior potency at higher concentrations. Notably, 27-deoxywithaferin A (2) significantly disrupted cell cycle distribution above 2.5 μM without dose dependence, whereas 5 μM 4-epi-5,6-deoxywithaferin A (4) induced phase-inconsistent cycle alterations. These findings highlight their antitumor potential and warrant further development.

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半合成27-脱氧内夫林A和4-epi-5,6-脱氧内夫林A作为潜在的抗肿瘤药物。

我们描述了两种简洁的三步合成路线，分别从withaferin A(1)合成27-脱氧withaferin A(2)和4-epi-5,6-脱氧withaferin A(4)。烯酮与噻吩的双键保护策略和环氧基的共轭还原是生成这些产品的重要因素，总收率为40%。用x射线晶体学证实了4-epi-5,6-脱氧内铁苷A(4)的绝对构型。27-Deoxywithaferin A（2)对MCF-7细胞的IC50值为顺铂的400倍（0.02 μM），而4-epi-5,6-deoxywithaferin A(4)的IC50值为1.73 ~ 4.27 μM）。这两种化合物都能剂量依赖性地抑制MCF-7细胞的增殖和诱导凋亡，其中4-epi-5,6-deoxywithaferin A(4)在较高浓度下表现出更强的效力。值得注意的是，27-deoxywithaferin A(2)明显破坏了2.5 μM以上的细胞周期分布，没有剂量依赖性，而5 μM - 4-epi-5,6-deoxywithaferin A(4)诱导了相不一致的周期改变。这些发现突出了它们的抗肿瘤潜力，值得进一步开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Natural Products 生物-药学

CiteScore

9.10

自引率

5.90%

发文量

294

审稿时长

2.3 months

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.