TY - JOUR
T1 - Stereochemical preference toward oncotarget
T2 - Design, synthesis and in vitro anticancer evaluation of diastereomeric β-lactams
AU - Olazarán-Santibáñez, Fabián
AU - Bandyopadhyay, Debasish
AU - Carranza-Rosales, Pilar
AU - Rivera, Gildardo
AU - Balderas-Rentería, Isaías
N1 - Publisher Copyright:
© Olazarán-Santibáñez et al.
PY - 2017
Y1 - 2017
N2 - Purpose: In the battle against cancer discovery of new and novel chemotherapeutic agent demands extreme obligation. Development of anticancer compounds with higher potency and reduced side-effects is timely and challenging. Experimental Design: A small series of fourteen diastereomeric β-lactams (seven pairs) were synthesized through multi-step process exploring [2+2] ketene-imine cycloaddition as the key step. Comparative stereochemical preferences were studied through computational docking and validated by in vitro evaluation. β-tubulin was considered as possible molecular target and in vitro anticancer evaluation was conducted against SiHa, B16F10, K562 and Chang cell lines. Caspase-3 activation assay and hematoxylin/eosin staining of the cells were also accomplished. Results: Better docking scores of the cis- over the trans-β-lactams indicated favorable β-lactam-β-tubulin interactions in cis-geometry. In vitro (IC50) evaluation confirmed better anticancer activity of the cis-diastereoisomers. Apoptosis-induced cell death was supported by caspase-3 activation study. A cis-β-lactam [(±)-Cis- 3-amino-1-phenyl-4-(p-tolyl) azetidin-2-one, 6C] was found to be more active (in vitro) than the marketed natural drug colchicine against SiHa and B16F10 (six times higher potency) cell lines. Reduced toxicity (compared to colchicine) in Chang cells confirmed better site-selectivity (accordingly less side-effects) of 6C than colchicine. Aside from 6C, most of the reported molecules demonstrated good to strong in vitro anticancer activity against SiHa and B16F10 cancer cell lines. Conclusions: Stereochemical preferences of the cis-β-lactams over their transcounterparts, toward the molecular target β-tubulin, was confirmed by docking studies and in vitro anticancer evaluation. Apoptosis was identified as the cause of cell death. The lead 6C exhibited higher potency and selectivity than the marketed drug colchicine both in silico as well as in vitro.
AB - Purpose: In the battle against cancer discovery of new and novel chemotherapeutic agent demands extreme obligation. Development of anticancer compounds with higher potency and reduced side-effects is timely and challenging. Experimental Design: A small series of fourteen diastereomeric β-lactams (seven pairs) were synthesized through multi-step process exploring [2+2] ketene-imine cycloaddition as the key step. Comparative stereochemical preferences were studied through computational docking and validated by in vitro evaluation. β-tubulin was considered as possible molecular target and in vitro anticancer evaluation was conducted against SiHa, B16F10, K562 and Chang cell lines. Caspase-3 activation assay and hematoxylin/eosin staining of the cells were also accomplished. Results: Better docking scores of the cis- over the trans-β-lactams indicated favorable β-lactam-β-tubulin interactions in cis-geometry. In vitro (IC50) evaluation confirmed better anticancer activity of the cis-diastereoisomers. Apoptosis-induced cell death was supported by caspase-3 activation study. A cis-β-lactam [(±)-Cis- 3-amino-1-phenyl-4-(p-tolyl) azetidin-2-one, 6C] was found to be more active (in vitro) than the marketed natural drug colchicine against SiHa and B16F10 (six times higher potency) cell lines. Reduced toxicity (compared to colchicine) in Chang cells confirmed better site-selectivity (accordingly less side-effects) of 6C than colchicine. Aside from 6C, most of the reported molecules demonstrated good to strong in vitro anticancer activity against SiHa and B16F10 cancer cell lines. Conclusions: Stereochemical preferences of the cis-β-lactams over their transcounterparts, toward the molecular target β-tubulin, was confirmed by docking studies and in vitro anticancer evaluation. Apoptosis was identified as the cause of cell death. The lead 6C exhibited higher potency and selectivity than the marketed drug colchicine both in silico as well as in vitro.
KW - Cancer
KW - Diastereoisomer
KW - Molecular docking
KW - β-Lactam
KW - β-Tubulin
UR - http://www.scopus.com/inward/record.url?scp=85020189038&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.18077
DO - 10.18632/oncotarget.18077
M3 - Artículo
C2 - 28562328
SN - 1949-2553
VL - 8
SP - 37773
EP - 37782
JO - Oncotarget
JF - Oncotarget
IS - 23
ER -