期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 20, 期 8, 页码 2603-2613出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.02.042
关键词
Breast cancer; Aromatase inhibitors; Isoflavanones
资金
- National Center for Research Resources from the National Institutes of Health [5P20RR016481-12]
- National Institute of General Medical Sciences from the National Institutes of Health [8 P20 GM103436-12]
- Center for Integrated Science and Mathematics (CINSAM)
- Northern Kentucky University Office of Research
Aromatase (CYP19) catalyzes the aromatization reaction of androgen substrates to estrogens, the last and rate-limiting step in estrogen biosynthesis. Inhibition of aromatase is a new and promising approach to treat hormone-dependent breast cancer. We present here the design and development of isoflavanone derivatives as potential aromatase inhibitors. Structural modifications were performed on the A and B rings of isoflavanones via microwave-assisted, gold-catalyzed annulation reactions of hydroxyaldehydes and alkynes. The in vitro aromatase inhibition of these compounds was determined by fluorescence-based assays utilizing recombinant human aromatase (baculovirus/insect cell-expressed). The compounds 3-(4-phenoxyphenyl)chroman-4-one (1h), 6-methoxy-3-phenylchroman-4-one (2a) and 3-(pyridin-3-yl)chroman-4-one (3b) exhibited potent inhibitory effects against aromatase with IC50 values of 2.4 mu M, 0.26 mu M and 5.8 mu M, respectively. Docking simulations were employed to investigate crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This report provides useful information on aromatase inhibition and serves as a starting point for the development of new flavonoid aromatase inhibitors. (C) 2012 Elsevier Ltd. All rights reserved.
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