Nieddu Valentina, Pinna Giansalvo, Marchesi Irene, Sanna Luca, Asproni Battistina, Pinna Gerard A, Bagella Luigi, Murineddu Gabriele
Department of Biomedical Sciences, and National Institute of Biostructures and Biosystems, University of Sassari , 07100 Sassari, Sardinia, Italy.
Department of Chemistry and Pharmacy, University of Sassari , Via Muroni 23, 07100 Sassari, Sardinia, Italy.
J Med Chem. 2016 Dec 8;59(23):10451-10469. doi: 10.1021/acs.jmedchem.6b00468. Epub 2016 Nov 29.
A series of novel 1,3,4-oxadiazoles was synthesized and evaluated for their cytotoxic activity in in vitro tumor models. Four of the new compounds (2d, 2j, 2k, and 2n) showed growth inhibition in the XTT dye assay. The most active agent, 2j, showed high potency against human cancer cells with ICs ranging from 0.05 to 1.7 μM. Preliminary SAR correlations suggested that the nature of chains on the oxadiazole is important for antitumor potency in vitro. Compound 2j determined a G/M arrest of the cell cycle and also activated a strong apoptotic response. The β-tubulin immunofluorescence analysis indicated that compound 2j effectively inhibited the microtubule organization in all cancer cell lines, causing the formation of abnormal spindle, which did not affect the normal human fibroblast cells NB1, Mrc-5 and IBR3. For all these reasons, compound 2j could be a good candidate in chemopreventive or chemotherapeutic strategies.
合成了一系列新型1,3,4 - 恶二唑，并在体外肿瘤模型中评估了它们的细胞毒性活性。四种新化合物（2d、2j、2k和2n）在XTT染料测定中显示出生长抑制作用。活性最高的试剂2j对人癌细胞显示出高效力，IC50范围为0.05至1.7 μM。初步的构效关系相关性表明，恶二唑上链的性质对体外抗肿瘤效力很重要。化合物2j导致细胞周期的G/M期阻滞，并激活了强烈的凋亡反应。β - 微管蛋白免疫荧光分析表明，化合物2j在所有癌细胞系中均有效抑制微管组织，导致异常纺锤体的形成，而这并不影响正常人成纤维细胞NB1、Mrc - 5和IBR3。基于所有这些原因，化合物2j可能是化学预防或化疗策略中的一个良好候选物。
