Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation

• Published in: Journal of natural products (Washington, D.C.) Vol. 81; no. 4; pp. 825 - 837
• Main Authors: Wijeratne, E. M. Kithsiri, Oliveira, Maria C. F, Mafezoli, Jair, Xu, Ya-Ming, Minguzzi, Sandro, Batista, Pedro H. J, Pessoa, Otília D. L, Whitesell, Luke, Gunatilaka, A. A. Leslie
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 27-04-2018
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.7b00918

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.