Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site.
Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site.
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β-内酰胺叠氮化物类似物作为靶向微管蛋白秋水仙碱位点的口服活性抗肿瘤剂的构效关系研究
DOI：
10.1038/s41598-017-12912-4
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发表时间：
2017-10-06
影响因子：
4.6
通讯作者：
Liu HM
中科院分区：
文献类型：
--
作者：
Fu DJ;Fu L;Liu YC;Wang JW;Wang YQ;Han BK;Li XR;Zhang C;Li F;Song J;Zhao B;Mao RW;Zhao RH;Zhang SY;Zhang L;Zhang YB;Liu HM
以微管蛋白秋水仙素结合位点为靶点，合成了一系列新型β-内酰胺叠氮衍生物，并对其构效关系进行了研究。其中化合物28对MGC-803细胞的增殖抑制作用最强，其IC 50值为0.106 μM，可诱导MGC-803细胞G2/M期阻滞和凋亡，并抑制上皮细胞向间质细胞转化。28通过与秋水仙碱位点结合而作为微管蛋白聚合的新型抑制剂。SAR分析表明，β-内酰胺-叠氮衍生物有效的抗增殖活性需要β-内酰胺C-3位的氢原子。化合物28的口服给药也有效地抑制了裸鼠体内MGC-803异种移植肿瘤的生长，而不引起体重的显著减轻。这些结果表明，化合物28是一种有前途的口服活性抗癌药物，具有进一步临床应用的潜力。
We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.
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