Synthesis and biological evaluation of new 2-methoxyestradiol derivatives: Potent inhibitors of angiogenesis and tubulin polymerization
Synthesis and biological evaluation of new 2-methoxyestradiol derivatives: Potent inhibitors of angiogenesis and tubulin polymerization
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DOI：
10.1016/j.bioorg.2021.104988
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发表时间：
2021-05-23
影响因子：
5.1
通讯作者：
Yu, Dequan
中科院分区：
文献类型：
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作者：
Sun, Moran;Zhang, Yixin;Yu, Dequan
在此，我们报道了一种天然化合物2-ME2(2-甲氧基雌二醇)的结构优化，该化合物在体内外对微管蛋白聚合、抗血管生成、MCF-7增殖和转移具有抑制活性但效力较低。合成了一系列新的3，17修饰和17修饰的2-ME2类似物，并研究了它们对MCF-7和其他五种不同的人类癌细胞株的抗增殖活性，从而发现了9i。9I与微管蛋白秋水仙碱结合紧密，抑制微管蛋白聚合，破坏细胞微管网络。细胞机制研究表明，9i通过下调p-CDc2、P21的表达，以剂量依赖的方式调控细胞凋亡相关蛋白(PARP、Caspase家族)，从而诱导G2/M期停滞。重要的是，9i显著抑制HUVEC管的形成、增殖、迁移和侵袭。斑马鱼异种移植实验证实了其对体内血管生成的抑制作用。此外，9i还能有效地抑制MCF-7细胞在体外和斑马鱼移植瘤中的增殖和转移。9i良好的物理化学性质和代谢稳定性进一步表明，它可以通过靶向微管蛋白秋水仙素结合部位，作为一种有效的抗血管生成、抑制乳腺癌增殖和转移的药物。
Here, we report the structural optimization of a hit natural compound, 2-ME2 (2-methoxyestradiol), which exhibited inhibitory activity but low potency on tubulin polymerization, antiangiogenesis, MCF-7 proliferation and metastasis in vitro and in vivo. A novel series of 3,17-modified and 17-modified analogs of 2-ME2 were synthesized and investigated for their antiproliferative activity against MCF-7 and another five different human cancer cell lines leading to the discovery of 9i. 9i bind to tubulin colchicine site tightly, inhibited tubulin polymerization and disrupted cellular microtubule networks. Cellular mechanism studies revealed that 9i could induce G2/M phase arrest by down-regulated expression of p-Cdc2, P21 and cell apoptosis by regulating apoptosis-related proteins (Parp, Caspase families) in a dose-dependent manner. Importantly, 9i significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 9i could effectively inhibit the proliferation and metastasis of MCF-7 cells in vitro and in zebrafish xenograft. The satisfactory physicochemical property and metabolic stability of 9i further indicated that it can act as a promising and potent anti-angiogenesis, inhibiting proliferation and metastasis of breast cancer agent via targeting tubulin colchicine binding site.