TY - JOUR
T1 - 3,5-Diaryl-1H-pyrazole as a molecular scaffold for the synthesis of apoptosis-inducing agents
AU - Shaw, Arthur Y.
AU - Liau, Hao Han
AU - Lu, Pei Jung
AU - Yang, Chia Ning
AU - Lee, Chien Hsing
AU - Chen, Jun Yan
AU - Xu, Zhigang
AU - Flynn, Gary
N1 - Funding Information:
Financial support from the National Science Council of the Republic of China and Tamkang University to A. Y. Shaw is gratefully acknowledged.
PY - 2010/5/1
Y1 - 2010/5/1
N2 - 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 GI50 values of 0.67, 0.89, 0.73 and 0.79 μM, 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 q2 and R2 values of 0.671 and 0.846, respectively.
AB - 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 GI50 values of 0.67, 0.89, 0.73 and 0.79 μM, 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 q2 and R2 values of 0.671 and 0.846, respectively.
UR - http://www.scopus.com/inward/record.url?scp=77951206607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951206607&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2010.03.016
DO - 10.1016/j.bmc.2010.03.016
M3 - Article
C2 - 20381360
AN - SCOPUS:77951206607
SN - 0968-0896
VL - 18
SP - 3270
EP - 3278
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 9
ER -