Purushottamachar Puranik - Potent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent.

Document created by Purushottamachar Puranik on Aug 22, 2014
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  Publication Details (including relevant citation   information):

  Bioorg Med Chem. 2008   Apr 1;16(7):3519-29. Epub 2008 Feb 14.


  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 microM). 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.



  Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/18316193