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

  • J Nat Prod. 2018 Apr 27;81(4):825-837. doi: 10.1021/acs.jnatprod.7b00918.
E M Kithsiri Wijeratne  1 ,  Maria C F Oliveira  1  2 ,  Jair Mafezoli  1  2 ,  Ya-Ming Xu  1 ,  Sandro Minguzzi  1  3 ,  Pedro H J Batista  2 ,  Otília D L Pessoa  2 ,  Luke Whitesell  4 ,  A A Leslie Gunatilaka  1
Affiliations
  • 1. Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences , University of Arizona , 250 E. Valencia Road , Tucson , Arizona 85706 , United States.
  • 2. Departamento de Química Orgânica e Inorgânica , Universidade Federal do Ceará , Campus do Pici, Caixa Postal 6044 , Fortaleza-CE , 60455-970 , Brazil.
  • 3. Curso de Química , Universidade Estadual de Mato Grosso do Sul , Unidade de Navirai, Rua Emilio Mascoli 275 , Navirai-MS , 79950-000 , Brazil.
  • 4. Whitehead Institute for Biomedical Research , 455 Main Street , Cambridge , Massachusetts 02142 , United States.
PMID: 29537263 DOI: 10.1021/acs.jnatprod.7b00918
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.

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