Oncotarget

Research Papers:

Stereochemical preference toward oncotarget: Design, synthesis and in vitro anticancer evaluation of diastereomeric β-lactams

Fabián Olazarán-Santibáñez, Debasish Bandyopadhyay _, Pilar Carranza-Rosales, Gildardo Rivera and Isaías Balderas-Rentería

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Oncotarget. 2017; 8:37773-37782. https://doi.org/10.18632/oncotarget.18077

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Abstract

Fabián Olazarán-Santibáñez1,2, Debasish Bandyopadhyay1, Pilar Carranza-Rosales3, Gildardo Rivera4, Isaías Balderas-Rentería2

1Department of Chemistry, The University of Texas-Rio Grande Valley, Edinburg, Texas, 78539, USA

2Universidad Autonoma de Nuevo Leon, Facultad de Ciencias Químicas, Ciudad Universitaria, San Nicolás de los Garza, Nuevo León, 64451, México

3Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, Nuevo León, 64700, México

4Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa, Tamaulipas, 88710, México

Correspondence to:

Debasish Bandyopadhyay, email: [email protected]

Isaías Balderas-Rentería, email: [email protected]

Keywords: β-Lactam, diastereoisomer, molecular docking, β-Tubulin, cancer

Received: March 06, 2017     Accepted: April 17, 2017     Published: May 22, 2017

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 [(±)-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 trans-counterparts, 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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