Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams
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...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
2017
|
| Subjects: | |
| Online Access: | http://eprints.uanl.mx/18207/1/498.pdf |
| _version_ | 1824415168893812736 |
|---|---|
| author | Olazarán Santibáñez, Fabián Eliseo Bandyopadhyay, Debasish Carranza Rosales, Pilar Rivera, Gildardo Balderas Rentería, Isaías |
| author_facet | Olazarán Santibáñez, Fabián Eliseo Bandyopadhyay, Debasish Carranza Rosales, Pilar Rivera, Gildardo Balderas Rentería, Isaías |
| author_sort | Olazarán Santibáñez, Fabián Eliseo |
| collection | Repositorio Institucional |
| description | 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 |
| format | Article |
| id | eprints-18207 |
| institution | UANL |
| language | English |
| publishDate | 2017 |
| record_format | eprints |
| spelling | eprints-182072020-05-29T15:57:13Z http://eprints.uanl.mx/18207/ Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams Olazarán Santibáñez, Fabián Eliseo Bandyopadhyay, Debasish Carranza Rosales, Pilar Rivera, Gildardo Balderas Rentería, Isaías QD Química 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 2017-05-22 Article PeerReviewed text en cc_by_nc_nd http://eprints.uanl.mx/18207/1/498.pdf http://eprints.uanl.mx/18207/1.haspreviewThumbnailVersion/498.pdf Olazarán Santibáñez, Fabián Eliseo y Bandyopadhyay, Debasish y Carranza Rosales, Pilar y Rivera, Gildardo y Balderas Rentería, Isaías (2017) Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams. Oncotarget, 8 (23). pp. 37773-37782. ISSN 1949-2553 http://doi.org/10.18632/oncotarget.18077 doi:10.18632/oncotarget.18077 |
| spellingShingle | QD Química Olazarán Santibáñez, Fabián Eliseo Bandyopadhyay, Debasish Carranza Rosales, Pilar Rivera, Gildardo Balderas Rentería, Isaías Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams |
| thumbnail | https://rediab.uanl.mx/themes/sandal5/images/online.png |
| title | Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams |
| title_full | Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams |
| title_fullStr | Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams |
| title_full_unstemmed | Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams |
| title_short | Stereochemical preference toward oncotarget: Design, synthesis and <i>in vitro</i> anticancer evaluation of diastereomeric β-lactams |
| title_sort | stereochemical preference toward oncotarget design synthesis and i in vitro i anticancer evaluation of diastereomeric x3b2 lactams |
| topic | QD Química |
| url | http://eprints.uanl.mx/18207/1/498.pdf |
| work_keys_str_mv | AT olazaransantibanezfabianeliseo stereochemicalpreferencetowardoncotargetdesignsynthesisandiinvitroianticancerevaluationofdiastereomericx3b2lactams AT bandyopadhyaydebasish stereochemicalpreferencetowardoncotargetdesignsynthesisandiinvitroianticancerevaluationofdiastereomericx3b2lactams AT carranzarosalespilar stereochemicalpreferencetowardoncotargetdesignsynthesisandiinvitroianticancerevaluationofdiastereomericx3b2lactams AT riveragildardo stereochemicalpreferencetowardoncotargetdesignsynthesisandiinvitroianticancerevaluationofdiastereomericx3b2lactams AT balderasrenteriaisaias stereochemicalpreferencetowardoncotargetdesignsynthesisandiinvitroianticancerevaluationofdiastereomericx3b2lactams |