Epoxide group relationship with cytotoxicity in withanolide derivatives from Withania somnifera

• Withania somnifera is an important medicinal plant of India.
• Its active constituents are withanolides, the C-28 ergostane steroids.
• Several derivatives obtained by modifications of the epoxide group have been prepared and tested for cytotoxicity.
• SAR revealed that epoxide plays important role in the cytotoxicity of withanolides.

Withania somnifera is one of the highly reputed medicinal plants of India. Its steroidal constituents exist in the form of two major substitution patterns, viz. withaferin A (1) and withanone (5). Withaferin A with oxidation at carbons 4, 5, and 6 is considered as an active type, especially as anticancer, whereas the withanones with oxidation at carbons 5, 6, and 7 rarely show any activity. We prepared a series of derivatives with modifications at carbons 5, 6, and 7 in ring B of these withanolides to study the role of the epoxide group towards the cytotoxic property of these bioactive steroids. We have converted withanolides into the respective thiiranes, amino alcohols and alcohols by selective reactions at the epoxide ring and were evaluated for in vitro anticancer activity against four cancer cell lines to study the structure activity relationships. The transformations of the epoxide group in withanolides of the withaferin A type showed moderate reduction in their cytotoxicity whereas the almost inactive withanones have shown some improvements in their alcohol derivatives.

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