Structure-activity relationships for withanolides as inducers of the cellular heat-shock response

E. M.Kithsiri Wijeratne, Ya Ming Xu, Ruth Scherz-Shouval, Marilyn T. Marron, Danilo D. Rocha, Manping X. Liu, Leticia V. Costa-Lotufo, Sandro Santagata, Susan Lindquist, Luke Whitesell, A. A.Leslie Gunatilaka

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30 Scopus citations

Abstract

To understand the relationship between the structure and the remarkably diverse bioactivities reported for withanolides, we obtained withaferin A (WA; 1) and 36 analogues (2-37) and compared their cytotoxicity to cytoprotective heat-shock-inducing activity (HSA). By analyzing structure-activity relationships for the series, we found that the ring A enone is essential for both bioactivities. Acetylation of 27-OH of 4-epi-WA (28) to 33 enhanced both activities, whereas introduction of β-OH to WA at C-12 (29) and C-15 (30) decreased both activities. Introduction of β-OAc to 4,27-diacetyl-WA (16) at C-15 (37) decreased HSA without affecting cytotoxicity, but at C-12 (36), it had minimal effect. Importantly, acetylation of 27-OH, yielding 15 from 1, 16 from 14, and 35 from 34, enhanced HSA without increasing cytotoxicity. Our findings demonstrate that the withanolide scaffold can be modified to enhance HSA selectively, thereby assisting development of natural product-inspired drugs to combat protein aggregation-associated diseases by stimulating cellular defense mechanisms.

Original languageEnglish (US)
Pages (from-to)2851-2863
Number of pages13
JournalJournal of Medicinal Chemistry
Volume57
Issue number7
DOIs
StatePublished - Apr 10 2014

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Wijeratne, E. M. K., Xu, Y. M., Scherz-Shouval, R., Marron, M. T., Rocha, D. D., Liu, M. X., Costa-Lotufo, L. V., Santagata, S., Lindquist, S., Whitesell, L., & Gunatilaka, A. A. L. (2014). Structure-activity relationships for withanolides as inducers of the cellular heat-shock response. Journal of Medicinal Chemistry, 57(7), 2851-2863. https://doi.org/10.1021/jm401279n