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

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Title Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents
 
Creator MISHRA, RC
GUNDALA, SR
KARNA, P
LOPUS, M
GUPTA, KK
NAGARAJU, M
HAMELBERG, D
TANDON, V
PANDA, D
REID, MD
ANEJA, R
 
Subject CANCER THERAPEUTICS
TUBULIN ISOTYPES
PERTURB MITOSIS
APOPTOSIS
RESISTANCE
CELLS
SURVIVIN
LYMPHOMA
TUMORS
Noscapine
Anticancer activity
Tubulin polymerization
 
Description 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 (K-D) for the interaction between tubulin and 2, 3, 4, 5 was found to be, 55 +/- 6 mu M, 44 +/- 6 mu M, 26 +/- 3 mu M, and 21 +/- 1 mu M 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. (C) 2015 Elsevier Ltd. All rights reserved.
 
Publisher PERGAMON-ELSEVIER SCIENCE LTD
 
Date 2016-01-14T13:08:53Z
2016-01-14T13:08:53Z
2015
 
Type Article
 
Identifier BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 25(10)2133-2140
0960-894X
1464-3405
http://dx.doi.org/10.1016/j.bmcl.2015.03.076
http://dspace.library.iitb.ac.in/jspui/handle/100/17577
 
Language en