3,5-Diaryl-1H-pyrazole as a molecular scaffold for the synthesis of apoptosis-inducing agents.
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.
Shaw
Arthur Y
AY
Department of Chemistry, Tamkang University, Taipei 251, Taiwan. shaw.299@gmail.com
Liau
Hao-Han
HH
Lu
Pei-Jung
PJ
Yang
Chia-Ning
CN
Lee
Chien-Hsing
CH
Chen
Jun-Yan
JY
Xu
Zhigang
Z
Flynn
Gary
G
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
D000970:Antineoplastic Agents; D011720:Pyrazoles; D011494:Protein Kinases