期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 7, 页码 3519-3529出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.02.031
关键词
anti-prostate cancer agents; sulfonamides; antiproliferative; structure-activity relationship (SAR)
资金
- NCI NIH HHS [R21 CA117991, R21 CA117991-01] Funding Source: Medline
- NIEHS NIH HHS [2T32ES007263-16A1] Funding Source: Medline
The search for novel androgen receptor (AR) down-regulating agents by catalyst HipHop pharmacophore modeling led to the discovery of some lead molecules. Unexpectedly, the effect of these leads on human prostate cancer LNCaP cell viability did not correlate with the ability of the compounds to cause down-regulation of AR protein expression. Through rational synthetic optimization of the lead compound (BTB01434), we have discovered a series of novel substituted diaryl molecules as potent anti-prostate cancer agents. Some compounds (1-6) were shown to be extremely potent inhibitors of LNCaP cell viability with GI(50) values in the nanomolar range (1.45-83 nM). The most potent compound (4-methylphenyl)[(4-methylphenyl) sulfonyl] amine (5) with a GI(50) value of 1.45 nM is 27,000 times more potent than our lead compound BTB01434 (GI(50) = 39.8 mu M). In addition, some of the compounds exhibited modest anti-androgenic activities and one was also a potent inhibitor (GI(50) = 850 nM) of PC-3 (AR-null) cell growth. A clear structure-activity relationship (SAR) has been established for activity against LNCaP cells, where potent molecules possess two substituted/unsubstituted aromatic rings connected through a sulfonamide linker. These novel compounds are strong candidates for development for the treatment of hormone-sensitive and importantly hormone-refractory prostate cancers in humans. (C) 2008 Elsevier Ltd. All rights reserved.
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