title: Potent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent.
abstract: 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.forename: Aakanksha
authors.initials: A
authors.lastname: Khandelwal
authors.forename: Tadas S
authors.initials: TS
authors.lastname: Vasaitis
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bruno
authors.forename: Lalji K
authors.initials: LK
authors.lastname: Gediya
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D000588:Amines; D059002:Androgen Receptor Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D007097:Imines; D011944:Receptors, Androgen