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

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TitlePotent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent.
Publication TypeJournal Article
Year of Publication2008
AuthorsPurushottamachar, P, Khandelwal, A, Vasaitis, TS, Bruno, RD, Gediya, LK, Njar, VCO
JournalBioorg Med Chem
Date Published2008 Apr 1
KeywordsAmines, Androgen Receptor Antagonists, Androgens, Antineoplastic Agents, Hormonal, Cell Line, Tumor, Cell Survival, Down-Regulation, Humans, Imines, Male, Models, Molecular, Molecular Structure, Prostatic Neoplasms, Receptors, Androgen, Structure-Activity Relationship, Transcription, Genetic

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.

Alternate JournalBioorg. Med. Chem.
PubMed ID18316193
Grant List2T32ES007263-16A1 / ES / NIEHS NIH HHS / United States
R21 CA117991-01 / CA / NCI NIH HHS / United States