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Synthesis of Uscharin Oxime Analogues and Their Biological Evaluation as HIF‐1 Inhibitors
Author(s) -
Zhou Xiaobo,
Xiao Riping,
Chen Ming,
Bai LiPing
Publication year - 2020
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.202003586
Subject(s) - chemistry , oxime , moiety , regioselectivity , stereochemistry , thiazoline , aldehyde , ether , hydroxylamine , medicinal chemistry , organic chemistry , catalysis
Uscharin‐like non‐classical cardenolides are considered to be useful as HIF‐1 inhibitors in the treatment of cancers. To develop more potent HIF‐1 inhibitors, oximes and oxime ethers of uscharin were designed and synthesized. Oximation of uscharin exhibited unexpectedly a regioselectivity and stereoselectivity at 3′‐thiazoline but not at the 19‐aldehyde group, since either E ‐ketoxime derivative 2 or its ether 5 at C‐3′ was found as the only product during oximation of uscharin using hydroxylamine or methoxyamine at room temperature. Two 19‐aldoxime derivatives 4 and 6 were also synthesized. Ketoxime analogue 2 showed more potent inhibitory effect on HIF‐1 transcriptional activity than the parental uscharin. Ketoxime ether 5 and 19‐aldoxime 6 exhibited stronger HIF‐1 suppressing effect than digoxin (the positive control drug). Moreover, ketoxime derivative 2 displayed the most potent anti‐proliferative activity against MCF‐7 cancer cells among all compounds. An analysis of structure‐activity relationship revealed that 3′‐ketoxime is a superior moiety to a thiazoline ring, while 19‐aldoxime is inferior to an aldehyde counterpart. Our findings may provide some guidance for the rational design of uscharin‐based promising HIF‐1 inhibitors.