| Sumario: | ABSTRACT
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 [(±)-Cis3-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
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