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, Leslie Gunatilaka

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

Fingerprint

Withanolides
Shock
Hot Temperature
Cytotoxicity
Cunninghamella
Heat-Shock Response
Cyclization
Epoxy Compounds
Structure-Activity Relationship
Scaffolds (biology)
Biotransformation
Bioactivity
Biological Products
Iodine
Assays
withaferin A
withanolide D

ASJC Scopus subject areas

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

Cite this

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

In: Journal of Natural Products, Vol. 81, No. 4, 27.04.2018, p. 825-837.

Research output: Contribution to journalArticle

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, Leslie. / Withaferin A and withanolide D analogues with dual heat-shock-inducing and cytotoxic activities : Semisynthesis and biological evaluation. In: Journal of Natural Products. 2018 ; Vol. 81, No. 4. pp. 825-837.
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