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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Mishra, Ram C.¹  Gundala, Sushma R.¹  Karna, Prasanthi¹  Lopus, Manu²  Gupta, Kamlesh K.³  Nagaraju, Mulpuri⁴  Hamelberg, Donald⁴  Tandon, Vibha^5,6  Panda, Dulal⁷  Reid, Michelle D.⁸  Aneja, Ritu¹ 

[1] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA

[2] UM DAE Ctr Excellence Basic Sci, Dept Expt Canc Therapeut & Chem Biol, Bombay 400098, Maharashtra, India

[3] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA

[4] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA

[5] Univ Delhi, Dept Chem, Delhi 110007, India

[6] Jawaharlal Nehru Univ, Special Ctr Mol Med, Delhi, India

[7] Indian Inst Technol, Dept Biosci & Bioengn, Bombay 400076, Maharashtra, India

[8] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA

关键词: Noscapine;    Anticancer activity;    Tubulin polymerization;   

DOI  :  10.1016/j.bmcl.2015.03.076

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free