期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 4, 页码 703-711出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.12.069
关键词
Steroid; Nitrile; Breast cancer; Hormone-independent breast cancer; Molecular docking; Ligand-based screening
资金
- Ministry of Education, Science and Technological Development of the Republic of Serbia [172021]
We report the synthesis of steroidal 16,17-seco-16,17a-dinitriles and investigate their antitumor cell properties. Compounds were evaluated for anticancer potential by in vitro antiproliferation studies, molecular docking and virtual screening. Several compounds inhibit the growth of breast and prostate cancer cell lines (MCF-7, MDA-MB-231 and PC3), and/or cervical cancer cells (HeLa). Supporting this, molecular docking predicts that steroidal 16,17-seco-16,17a-dinitriles could bind with high affinity to multiple molecular targets of breast and prostate cancer treatment (aromatase, estrogen receptor alpha, androgen receptor and 17 alpha-hydroxylase) facilitated by D-seco flexibility and nitrile-mediated contacts. Thus, 16,17-seco-16,17a-dinitriles may be useful for the design of inhibitors of multiple steroidogenesis pathways. Strikingly, 10, a 1,4-dien-3-on derivative, displayed selective submicromolar antiproliferative activity against hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cells (IC50 0.52, 0.11 mu M, respectively). Ligand-based 3D similarity searches suggest AKR1C, 17 beta-HSD and/or 3 beta-HSD subfamilies as responsible for this antiproliferative activity, while fast molecular docking identified AKR1C and ER beta as potential binders-both targets in the treatment of hormone-independent breast cancers. (c) 2015 Elsevier Ltd. All rights reserved.
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