With an aim to develop new curcumin inspired analogues as potent anticancer agents, we synthesized a series of (1E,4E)-1-phenyl-5-(3-phenylimidazo[1,2-a]pyridin-2-yl)penta-1,4-dien-3-ones (12a–t) as tubulin polymerization inhibitors. An initial screening was carried out to evaluate their cytotoxic potential on a panel of six cancer cell lines namely, cervical (HeLa), gastric (HGC-27), lung (NCI-H460), prostate (DU-145 and PC-3) and breast (4T1), using MTT assay. Among the compounds tested, compounds 12e, 12r and 12t showed potent growth inhibition and 12t {(1E,4E)-1-(3-(3,4-difluorophenyl)imidazo[1,2-a]pyridin-2-yl)-5-(2,4,6-trimethoxyphenyl)penta-1,4-dien-3-one} being the most active member of the series inhibited the growth of all the tested cell lines with IC₅₀ values varying from 1.7 – 2.97 μM. Moreover, 12t showed promising cytotoxicity on PC-3, HGC-27 and HeLa cell lines with IC₅₀ values of 2.11 ± 0.27 μM, 2.21 ± 0.25 μM and 2.53 ± 0.01 μM respectively. The results from aqueous solubility test showed that compounds 12e and 12t have 1.7 and 2.8 times more aqueous solubility than curcumin. Interestingly, the most active compound 12t was found to be nearly 2 times more selective on PC-3 cells as well as safe on normal human prostate (RWPE-1) cells. In addition, compound 12t efficiently inhibited tubulin polymerization with IC₅₀ value of 8.44 ± 0.13 μM and molecular modelling studies disclosed that 12t binds at the colchicine binding site of the tubulin. Cell cycle analysis revealed that 12t arrests PC-3 cells in G2/M phase in a dose dependant manner. Further, treatment of PC-3 cells with 12t showed typical apoptotic morphology, also led to the impairment of mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS). Altogether, the results from acridine orange/ethidium bromide (AO-EB) and DAPI staining studies, annexin V-FITC/propidium iodide staining assay, analysis of mitochondrial membrane potential (DΨm) and reactive oxygen species (ROS) levels undoubtedly demonstrated the induction of apoptosis in PC-3 cells by compound 12t.

为了开发新的姜黄素激发类似物作为有效的抗癌药，我们合成了一系列（1 E，4 E）-1-苯基-5-（3-苯基咪唑并[1,2- a ]吡啶-2-基） penta-1,4-dien-3-ones（12a–t）作为微管蛋白聚合抑制剂。初步筛选以评估其对六种癌细胞系的细胞毒性潜力，这六种癌细胞系分别是宫颈癌（HeLa），胃癌（HGC-27），肺癌（NCI-H460），前列腺癌（DU-145和PC-3）和乳房（4T1），使用MTT分析。在测试的化合物中，化合物12e，12r和12t显示出有效的生长抑制作用，而12t {（1 E，4 E）-1-（3-（3,4-二氟苯基）咪唑并[1,2 - a ]吡啶-2-基）-5-（2,4,6-三甲氧基苯基）penta-1,4-dien-3-一个}是该系列中最活跃的成员，抑制了所有测试细胞系的生长，IC ₅₀值在1.7 – 2.97μM之间变化。此外，12t对PC-3，HGC-27和HeLa细胞系显示出有希望的细胞毒性，IC ₅₀值分别为2.11±0.27μM，2.21±0.25μM和2.53±0.01μM。水溶性试验的结果表明，化合物12e和12t的水溶性是姜黄素的1.7和2.8倍。有趣的是，活性最高的化合物12t发现对PC-3细胞的选择性高出近2倍，对正常人前列腺（RWPE-1）细胞的安全性也高。此外，化合物12t有效抑制微管蛋白聚合，IC ₅₀值为8.44±0.13μM，分子模型研究表明12t在微管蛋白的秋水仙碱结合位点结合。细胞周期分析表明，12t以剂量依赖性方式将PC-3细胞阻滞在G2 / M期。此外，用12t处理PC-3细胞表现出典型的细胞凋亡形态，还导致线粒体膜电位（DΨm）受损和活性氧（ROS）水平升高。总之，from啶橙/溴化乙锭（AO-EB）和DAPI染色研究，膜联蛋白V-FITC /碘化丙啶染色测定，线粒体膜电位（DΨm）和活性氧（ROS）水平分析的结果无疑证明了诱导作用。化合物12t对PC-3细胞凋亡的影响Apoptosis 。