The Semisynthesis of 27-Deoxywithaferin A and 4-<i>epi</i>-5,6-Deoxywithaferin A from Withaferin A as Potential Antitumor Agents

We describe two concise, three-step routes for the individual synthesis of 27-deoxywithaferin A (<b>2</b>) and 4-<i>epi</i>-5,6-deoxywithaferin A (<b>4</b>) from withaferin A (<b>1</b>). 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-<i>epi</i>-5,6-deoxywithaferin A (<b>4</b>) has been confirmed by X-ray crystallography. 27-Deoxywithaferin A (<b>2</b>) exhibited a 400-fold higher potency than cisplatin against MCF-7 cells (IC₅₀ = 0.02 μM), while 4-<i>epi</i>-5,6-deoxywithaferin A (<b>4</b>) displayed variable IC₅₀ values (1.73-4.27 μM). Both compounds dose-dependently suppressed proliferation and induced apoptosis in MCF-7 cells, with 4-<i>epi</i>-5,6-deoxywithaferin A (<b>4</b>) demonstrating superior potency at higher concentrations. Notably, 27-deoxywithaferin A (<b>2</b>) significantly disrupted cell cycle distribution above 2.5 μM without dose dependence, whereas 5 μM 4-<i>epi</i>-5,6-deoxywithaferin A (<b>4</b>) induced phase-inconsistent cycle alterations. These findings highlight their antitumor potential and warrant further development.