Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents
Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents
复制标题
DOI：
10.1021/acs.jmedchem.5b01086
复制
发表时间：
2016-01-14
影响因子：
7.3
通讯作者：
Meegan, Mary J.
中科院分区：
文献类型：
--
作者：
Greene, Thomas F.;Wang, Shu;Meegan, Mary J.
研究了一系列3-苯氧基-1，4-二芳基-2-酮的构效关系，发现了一些有效的抗增殖化合物，包括trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3，4，5-trimethoxyphenyl)azetidin-2-one(78b)和trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3，4，5-trimethoxyphenyl)azetidin-2-one(90b)。X射线结晶学研究表明，1-苯基A环和4-苯基B环之间的扭转角对于有效的抗增殖活性具有潜在的重要性，并且3-苯氧基和4-苯环之间的反式构型通常是最佳的。这些化合物对MCF-7乳腺癌细胞的IC50值分别为38和19 nM，抑制体外培养的微管蛋白聚合，破坏MCF-7细胞的微管结构，引起细胞G(2)/M期停滞和细胞凋亡。化合物90b在NCI60细胞筛选中的GI50值平均为22 nM，细胞毒性最小，并与秋水仙碱结合部位相互作用。合成了78b和90b的磷酸和氨基酸前体药物，其中丙氨酸酰胺102B保留了活性，是一种很有前途的临床开发候选药物。
Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl A ring and 4-phenyl B ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G(2)/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on beta-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.