Kamal Ahmed, Balakrishna Moku, Nayak V Lakshma, Shaik Thokhir Basha, Faazil Shaikh, Nimbarte Vijaykumar D
Medicinal Chemistry & Pharmacology, Council of Science and Industrial Research, Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500 007 (India); Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad-500 037 (India).
ChemMedChem. 2014 Dec;9(12):2766-80. doi: 10.1002/cmdc.201402310. Epub 2014 Oct 14.
A series of chalcone conjugates featuring the imidazo[2,1-b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF-7, A549, HeLa, DU-145 and HT-29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 μM. Among them, (E)-3-(6-(4-fluorophenyl)-2,3-bis(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)-1-(pyridin-2-yl)prop-2-en-1-one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell-cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase-3, DNA fragmentation analysis, and Annexin V-FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein.
设计、合成了一系列具有咪唑并[2,1 - b]噻唑骨架的查尔酮共轭物，并评估了它们对五种人类癌细胞系（MCF - 7、A549、HeLa、DU - 145和HT - 29）的细胞毒性活性。这些新型杂合分子显示出有前景的细胞毒性活性，IC50值范围为0.64至30.9 μM。其中，(E)-3-(6-(4 - 氟苯基)-2,3 - 双(4 - 甲氧基苯基)咪唑并[2,1 - b]噻唑 - 5 - 基)-1-(吡啶 - 2 - 基)丙 - 2 - 烯 - 1 - 酮（化合物11x）在所有测试细胞系中均显示出强效的抗增殖活性，IC50值范围为0.64至1.44 μM。为了研究其作用机制，在A549肺癌细胞系上对这种有前景的共轭物（化合物11x）进行了详细的生物学研究。微管蛋白聚合试验和免疫荧光分析结果表明，该共轭物能有效抑制A549细胞中的微管组装。流式细胞术分析显示，该共轭物诱导细胞周期停滞在G2/M期并导致凋亡性细胞死亡。Hoechst染色、caspase - 3激活、DNA片段化分析和膜联蛋白V - FITC检测进一步证实了这一点。此外，分子对接研究表明，该共轭物（化合物11x）与微管蛋白高效相互作用并结合。
