title: 3,5-Diaryl-1H-pyrazole as a molecular scaffold for the synthesis of apoptosis-inducing agents.
abstract: The scaffold of 3,5-diaryl-1H-pyrazole was selected as a molecular template to synthesize novel growth-inhibitory agents in the present study. Our findings suggested that analogs bearing electron-withdrawing groups on one ring while electron-donating groups on another reveal significant activities. In particular, 26 bearing a 1,1'-biphenyl moiety displayed the most potent activity against OVCA, SW620, H460 and AGS cells with GI(50) values of 0.67, 0.89, 0.73 and 0.79 microM, respectively. The mechanistic study revealed that 26-mediated apoptosis-inducing effect on OVCA cells was, in part, attributed to the inhibition of protein kinase B/Akt activity, accompanied by the mitochondrial apoptotic pathway through the activation of caspase-9, caspase-3, as well as the cleavage of protein poly(ADP-ribose) polymerase (PARP) and DNA fragmentation. Further structure-activity relationship study employed by Comparative Molecular Field Analysis (CoMFA) was carried out with q(2) and R(2) values of 0.671 and 0.846, respectively.
authors.affiliation: Department of Chemistry, Tamkang University, Taipei 251, Taiwan. shaw.299@gmail.com
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Shaw
authors.forename: Hao-Han
authors.initials: HH
authors.lastname: Liau
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Yang
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Lee
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Chen
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xu
authors.forename: Gary
authors.initials: G
authors.lastname: Flynn
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011494:Protein Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011494:Protein Kinases