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Bioorg Med Chem Lett. 2015;25(10):2133-40. doi: 10.1016/j.bmcl.2015.03.076. Epub 2015 Mar 31.

Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents.

Author information

1
Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
2
Department of Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences, Kalina, Mumbai 400098, India.
3
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
4
Department of Chemistry, Georgia State University, Atlanta, GA, USA.
5
Department of Chemistry, University of Delhi, Delhi, India; Special Centre of Molecular Medicine, Jawaharlal Nehru University, Delhi, India.
6
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
7
Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
8
Department of Biology, Georgia State University, Atlanta, GA 30303, USA. Electronic address: raneja@gsu.edu.

Abstract

Noscapine is an opium-derived kinder-gentler microtubule-modulating drug, currently in Phase I/II clinical trials for cancer chemotherapy. Here, we report the synthesis of four more potent di-substituted brominated derivatives of noscapine, 9-Br-7-OH-NOS (2), 9-Br-7-OCONHEt-NOS (3), 9-Br-7-OCONHBn-NOS (4), and 9-Br-7-OAc-NOS (5) and their chemotherapeutic efficacy on PC-3 and MDA-MB-231 cells. The four derivatives were observed to have higher tubulin binding activity than noscapine and significantly affect tubulin polymerization. The equilibrium dissociation constant (KD) for the interaction between tubulin and 2, 3, 4, 5 was found to be, 55±6μM, 44±6μM, 26±3μM, and 21±1μM respectively, which is comparable to parent analog. The effects of these di-substituted noscapine analogs on cell cycle parameters indicate that the cells enter a quiescent phase without undergoing further cell division. The varying biological activity of these analogs and bulk of substituent at position-7 of the benzofuranone ring system of the parent molecule was rationalized utilizing predictive in silico molecular modeling. Furthermore, the immunoblot analysis of protein lysates from cells treated with 4 and 5, revealed the induction of apoptosis and down-regulation of survivin levels. This result was further supported by the enhanced activity of caspase-3/7 enzymes in treated samples compared to the controls. Hence, these compounds showed a great potential for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers.

KEYWORDS:

Anticancer activity; Noscapine; Tubulin polymerization

PMID:
25891106
PMCID:
PMC4465564
DOI:
10.1016/j.bmcl.2015.03.076
[Indexed for MEDLINE]
Free PMC Article

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