Design, synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents
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- 作者：G. Bharath Kumar<sup>asup> ; V. Lakshma Nayak<sup>asup> ; Ibrahim Bin Sayeed<sup>asup> ; Vangala Santhosh Reddy<sup>asup> ; Anver Basha Shaik<sup>asup> ; Rasala Mahesh<sup>asup> ; Mirza Feroz Baig<sup>asup> ; Mohd Adil Shareef<sup>asup> ; A. Ravikumar<sup>bsup> ; 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>
- 关键词：Phenstatin/isocombretastatin-oxindole ; Tubulin depolymerization ; Annexin V-FITC and mitochondrial membrane depolarization
- 刊名：Bioorganic & Medicinal Chemistry
- 出版年：2016
- 出版时间：15 April 2016
- 年：2016
- 卷：24
- 期：8
- 页码：1729-1740
- 全文大小：2056 K
文摘
A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC<sub>50sub> values ranging from 0.049 to 38.90 μM. Amongst them, two conjugates (<strong class="boldFont">5cstrong> and <strong class="boldFont">5dstrong>) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC<sub>50sub> value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC<sub>50sub> values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (<strong class="boldFont">5cstrong> and <strong class="boldFont">5dstrong>) arrest at the G<sub>2sub>/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly <strong class="boldFont">5cstrong> and <strong class="boldFont">5dstrong> exhibit significant inhibitory effect on the tubulin assembly with an IC<sub>50sub> value of 1.23 μM and 1.01 μM, respectively. Molecular docking studies indicated that these compounds (<strong class="boldFont">5cstrong> and <strong class="boldFont">5dstrong>) occupy the colchicine binding site of the tubulin.