Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents. Issue 10 (15th May 2015)

• Record Type: Journal Article
• Authors: Mishra, Ram C.; Gundala, Sushma R.; Karna, Prasanthi; Lopus, Manu; Gupta, Kamlesh K.; Nagaraju, Mulpuri; Hamelberg, Donald; Tandon, Vibha; Panda, Dulal; Reid, Michelle D.; Aneja, Ritu
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 10(2015)
• Page Start: 2133
• Page End: 2140
• Publication Date: 2015-05-15
• Subjects: FBS fetal bovine serum -- ATCC American type cell culture -- MTT tetrazolium bromide solution -- DNA deoxyribonucleic acid -- DMSO dimethylsulfoxide -- IC50 inhibitory concentration 50% -- Nos noscapine -- EM011 bromonoscapine -- PBS phosphate buffered saline -- KD dissociation constant -- FACS fluorescence-activated cell sorting -- PARP poly ADP ribose polymerase; Noscapine -- Anticancer activity -- Tubulin polymerization; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.076
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 ( K D ) for the interaction between tubulin and2, 3, 4, 5 was found to be, 55 ± 6 μM, 44 ± 6 μM, 26 ± 3 μM, and 21 ± 1 μM 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 with4 and5, 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.