Design, synthesis and biological evaluation of novel 2-methoxyestradiol analogs as dual selective estrogen receptor modulators (SERMs) and antiangiogenic agents
Design, synthesis and biological evaluation of novel 2-methoxyestradiol analogs as dual selective estrogen receptor modulators (SERMs) and antiangiogenic agents
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作为双重选择性雌激素受体调节剂（SERM）和抗血管生成剂的新型 2-甲氧基雌二醇类似物的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2017.08.016
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发表时间：
2017-10-20
影响因子：
6.7
通讯作者：
Xiang, Hua
中科院分区：
文献类型：
--
作者：
Lao, Kejing;Wang, Yejun;Xiang, Hua
2-甲氧基雌二醇是一种兼具抗血管生成和血管破坏作用的新型药物。本研究针对ERα和微管蛋白，设计并合成了11个α取代的2-甲氧基雌二醇类似物。对其对5种不同细胞株的抗增殖活性进行了生物学评价。结果表明，大多数化合物都有较好的活性，其中化合物24c和30c的活性最好，在所有细胞系中的微摩尔IC50都很低(2.73mU M-7.75mM)。内质网亲和力研究表明，大多数化合物在50 mU M时表现出较好的活性。在进一步的机制研究中，观察到24c和30c可以诱导G2/M细胞周期停滞，并具有显著的抗雌激素活性。在CAM实验中，化合物24c和30c具有明显的抗血管生成活性，与2-甲氧基雌二醇相当。总体而言，根据生物活性数据，24c和30c可以被确定为一个潜在的先导分子，可能对癌症治疗具有重要的治疗意义。(C)2017年爱思唯尔·马森公司。版权所有。
2-methoxyestradiol is a novel agent showing both anti-angiogenic and vascular disrupting properties. In this study, a series of 11 alpha-substituted 2-methoxyestradiol analogs have been designed and synthesized targeting dual ER alpha and microtubulin. Biological evaluation was performed on their anti-proliferative activities against 5 different cell lines. The results indicated that most compounds exhibited good activities, in which compound 24c and 30c showed the best activity with low micromolar IC50 (2.73 mu M -7.75 mu M) in all cell lines. The investigation of ER affinity showed that the majority of the compounds displayed good activity at the concentration of 50 mu M. In further mechanism study, it was observed that 24c and 30c could induce G2/M cell cycle arrest as well as significant anti-estrogenic activity. In CAM assay, compound 24c and 30c presented significantly anti-angiogenesis activity comparable with 2-methoxyestradiol. Overall, based on biological activities data, 24c and 30c can be identified as a potential lead molecule which might be of therapeutic importance for cancer treatment. (C) 2017 Elsevier Masson SAS. All rights reserved.