Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents
详细信息 查看全文
- 作者：Ahmed Kamal<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>csup><sup> ; sup><sup>ahmedkamal@iict.res.in" class="auth_mail" title="E-mail the corresponding authorsup> ; Shaik Bajee<sup>asup> ; Vadithe Lakshma Nayak<sup>asup> ; Ayinampudi Venkata Subba Rao<sup>asup> ; Burri Nagaraju<sup>asup> ; Challa Ratna Reddy<sup>asup> ; Kapure Jeevak Sopanrao<sup>bsup> ; Abdullah Alarifi<sup>csup>
- 关键词：CA-4 ; Cinnamides ; Conjugate ; Cytotoxicity ; Cell cycle ; Tubulin polymerization
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：15 June 2016
- 年：2016
- 卷：26
- 期：12
- 页码：2957-2964
- 全文大小：2610 K
文摘
A series of new molecules have been designed based on a hybridization approach by combining the arylcinnamide and combretastatin pharmacophores. These were synthesized and evaluated for their cytotoxic activity, effect on inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant cytotoxic activity against some representative human cancer cell lines and two of the conjugates <strong class="boldFont">6istrong> and <strong class="boldFont">6pstrong> displayed potent cytotoxicity with GI<sub>50sub> values of 56 nM and 31 nM respectively against the human breast cancer cell line (MCF-7). SAR studies revealed that 3,4-substitution on the phenyl ring of the cinnamide moiety is beneficial for enhanced cytotoxicity. Moreover, G2/M cell cycle arrest was induced by these conjugates (<strong class="boldFont">6istrong> and <strong class="boldFont">6pstrong>) apart from tubulin polymerization inhibition (IC<sub>50sub> of 1.97 μM and 1.05 μM respectively). Further, mitochondrial membrane potential, Annexin V-FITC and caspase-9 activation assays suggested that these conjugates induce cell death by apoptosis. Docking studies revealed that these conjugates interact and bind at the colchicine binding site of the tubulin.