Design, synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents

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• 作者：G. Bharath Kumar^a ; V. Lakshma Nayak^a ; Ibrahim Bin Sayeed^a ; Vangala Santhosh Reddy^a ; Anver Basha Shaik^a ; Rasala Mahesh^a ; Mirza Feroz Baig^a ; Mohd Adil Shareef^a ; A. Ravikumar^b ; Ahmed Kamal^a ; ^b ; ^c ; ^{ahmedkamal@iict.res.in" class="auth_mail" title="E-mail the corresponding author}
• 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 IC₅₀ values ranging from 0.049 to 38.90 μM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC₅₀ value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC₅₀ values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G₂/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 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC₅₀ value of 1.23 μM and 1.01 μM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin.