TY - JOUR
T1 - Withaferin A and withanolide D analogues with dual heat-shock-inducing and cytotoxic activities
T2 - Semisynthesis and biological evaluation
AU - Wijeratne, E. M.Kithsiri
AU - Oliveira, Maria C.F.
AU - Mafezoli, Jair
AU - Xu, Ya Ming
AU - Minguzzi, Sandro
AU - Batista, Pedro H.J.
AU - Pessoa, Otília D.L.
AU - Whitesell, Luke
AU - Gunatilaka, A. A.Leslie
N1 - Publisher Copyright:
© 2018 American Chemical Society and American Society of Pharmacognosy.
PY - 2018/4/27
Y1 - 2018/4/27
N2 - 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.
AB - 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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U2 - 10.1021/acs.jnatprod.7b00918
DO - 10.1021/acs.jnatprod.7b00918
M3 - Article
C2 - 29537263
AN - SCOPUS:85046076548
SN - 0163-3864
VL - 81
SP - 825
EP - 837
JO - Journal Of Natural Products
JF - Journal Of Natural Products
IS - 4
ER -