Withaferin A and withanolide D analogues with dual heat-shock-inducing and cytotoxic activities: Semisynthesis and biological evaluation

E. M.Kithsiri Wijeratne, Maria C.F. Oliveira, Jair Mafezoli, Ya Ming Xu, Sandro Minguzzi, Pedro H.J. Batista, Otília D.L. Pessoa, Luke Whitesell, A. A.Leslie Gunatilaka

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)825-837
Number of pages13
JournalJournal Of Natural Products
Volume81
Issue number4
DOIs
StatePublished - Apr 27 2018

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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