Anchoori Ravi Kumar, Kortenhorst Madeleine Susanne Quirine, Hidalgo Manuel, Sarkar Taradas, Hallur Gurulingappa, Bai Ruoli, Diest Paul J Van, Hamel Ernest, Khan Saeed R
Division of Chemical Therapeutics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
J Med Chem. 2008 Oct 9;51(19):5953-7. doi: 10.1021/jm800203e. Epub 2008 Sep 9.
Current microtubule inhibitory agents used in the clinic to treat cancer have severe side effects, and development of resistance is frequent. We have evaluated the antitumor effect of a novel 30-compound library of phenoxy pyridine and phenyl sulfanyl pyridine derivatives. MTT assays revealed that, of all 30 compounds tested, compounds 2 and 3 showed the largest decrease in proliferation (low muM range) against Panc1 and HS766T human pancreatic cancer cells. Flow cytometry experiments with MCF7 breast cancer cells showed a G2/M arrest comparable to that of colcemid. Immunofluorescence staining demonstrated complete disappearance of intracellular microtubules. Tubulin assembly assays, however, showed a dose-dependent decrease in tubulin assembly with compound 3 that seemed limited to about 50% of the control reaction. With compound 2 treatment, there was only a delay in the onset of assembly, with no effect on the extent of the reaction. Taken together, our results show that these novel microtubule inhibitors have promising anticancer activity and can be potentially used to overcome paclitaxel resistance in the clinical setting.
目前临床上用于治疗癌症的微管抑制药物具有严重的副作用，而且耐药性频繁出现。我们评估了一个由30种苯氧基吡啶和苯基硫烷基吡啶衍生物组成的新型化合物库的抗肿瘤效果。MTT分析表明，在所测试的30种化合物中，化合物2和3对Panc1和HS766T人胰腺癌细胞的增殖抑制作用最大（低 microM范围）。对MCF7乳腺癌细胞进行的流式细胞术实验显示，其G2/M期阻滞与秋水仙酰胺相当。免疫荧光染色显示细胞内微管完全消失。然而，微管蛋白组装分析表明，化合物3使微管蛋白组装呈剂量依赖性减少，似乎仅限于对照反应的约50%。用化合物2处理时，只是组装起始延迟，对反应程度没有影响。综上所述，我们的结果表明，这些新型微管抑制剂具有有前景的抗癌活性，并且在临床环境中有可能用于克服紫杉醇耐药性。
