Pharmacological exploitation of the peroxisome proliferator-activated receptor gamma agonist ciglitazone to develop a novel class of androgen receptor-ablative agents.
On the basis of our finding that the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist ciglitazone at high doses was able to mediate PPARgamma-independent transcriptional repression of androgen receptor (AR) in a tumor cell-specific manner, we used Delta2CG, a PPARgamma-inactive analogue of ciglitazone, to conduct lead optimization to develop a novel class of AR-ablative agents. Structure-activity analysis indicates a high degree of flexibility in realigning Delta2CG's structural moieties without compromising potency in AR repression, as evidenced by the higher AR-ablative activity of the permuted isomer 9 [( Z)-5-(4-hydroxybenzylidene)-3-(1-methylcyclohexylmethyl)thiazolidine-2,4-dione]. Further modifications of 9 gave rise to 12 [( Z)-5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-(1-methylcyclohexylmethyl)thiazolidine-2,4-dione], which completely inhibited AR expression in LNCaP cells at low micromolar concentrations. This AR down-regulation led to growth inhibition in LNCaP cells through apoptosis induction. Moreover, the role of AR repression in the antiproliferative effect of compound 12 was validated by the differential inhibition of cell viability between androgen-responsive and androgen-nonresponsive cells.
Yang
Jian
J
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Wei
Shuo
S
Wang
Da-Sheng
DS
Wang
Yu-Chieh
YC
Kulp
Samuel K
SK
Chen
Ching-Shih
CS
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology*; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D011944:Receptors, Androgen; D045162:Thiazolidinediones; C039671:ciglitazone