Synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers

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• 作者：A.V. Subba Rao^a ; ^b ; Konderu Swapna^c ; Siddiq Pasha Shaik^a ; ^b ; V. Lakshma Nayak^a ; T. Srinivasa Reddy^c ; Satish Sunkari^a ; ^b ; Thokhir Basha Shaik^a ; Chandrakant Bagul^c ; Ahmed Kamal^a ; ^b ; ^c ;
• 关键词：Combretastatin A-4 ; Benzothiazole ; Triazoles and tetrazoles ; Antiproliferative activity ; Tubulin polymerization ; Colchicine competition assay ; Apoptosis
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：977-999
• 全文大小：4686 K
• 卷排序：25

文摘

A series of colchicine site binding tubulin inhibitors were synthesized by the modification of the combretastatin pharmacophore. The ring B was replaced by the pharmacologically relevant benzothiazole scaffolds, and the cis configuration of the olefinic bond was restricted by the incorporation of a triazole and tetrazole rings which is envisaged by the structural resemblance to a tubulin inhibitor like combretastatin (CA-4). These compounds were evaluated for their antiproliferative activity on selected cancer cell lines and an insight in the structure activity relationship was developed. The most potent compounds (9a and 9b) demonstrated an antiproliferative effect comparable to that of CA-4. Mitotic cell cycle arrest in G2/M phase revealed the disruption of microtubule dynamics that was confirmed by tubulin polymerization assays and immunocytochemistry studies at the cellular level. Western blot analysis revealed that these compounds accumulate more tubulin in the soluble fraction. The colchicine competitive binding assay and the molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of CA-4. Moreover, the triggering of apoptotic cell death after mitotic arrest was investigated by studying their effect by Hoechst staining, Annexin-V-FITC assay, mitochondrial membrane potential, ROS generation and caspase-3 activation.