2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: Synthesis, in vitro SAR, protein crystallography, and in vivo activity
2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: Synthesis, in vitro SAR, protein crystallography, and in vivo activity
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DOI：
10.1021/jm060705x
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发表时间：
2006-12-28
影响因子：
7.3
通讯作者：
Potter, Barry V. L.
中科院分区：
文献类型：
--
作者：
Leese, Mathew P.;Leblond, Bertrand;Potter, Barry V. L.
本文讨论了雌二醇-17-O-氨基磺酸酯和雌二醇3，17-O，O-双氨基磺酸酯（E2 bisMATE）作为甾体硫酸酯酶（STS）抑制剂和抗增殖剂的抗癌活性和SAR。与17-O-单氨基磺酸酯11相比，E13，17-O，O-双氨基磺酸酯20和21被证明是优异的STS抑制剂。2-取代的E2 bisMATE 21和23还表现出有效的抗增殖活性，在NCI 60细胞系组中的平均图中点值为18-87 nM。21例在早期刘易斯肺模型中表现出体外和体内抗血管生成活性，23例经口给药。在裸鼠异种移植肿瘤模型中引起显著的生长抑制。建模研究表明，E2 bisMATEs和2-MeOE 2共享一个共同的模式结合微管蛋白，虽然比较分析的活动概况是负面的。21与碳酸酐酶II共结晶，X射线晶体学揭示了21的17-O-氨基磺酸盐与活性位点锌和可能的额外较低亲和力结合位点的意外配位。2-取代的E2 bisMATE是进一步开发为多靶点抗癌剂的有吸引力的候选物。
The anticancer activities and SARs of estradiol-17-O-sulfamates and estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) as steroid sulfatase (STS) inhibitors and antiproliferative agents are discussed. Estradiol 3,17-O,O-bis-sulfamates 20 and 21, in contrast to the 17-O-monosulfamate 11, proved to be excellent STS inhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity with mean graph midpoint values of 18-87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growth inhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and 2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles was negative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpected coordination of the 17-O-sulfamate of 21 to the active site zinc and a probable additional lower affinity binding site. 2-Substituted E2bisMATEs are attractive candidates for further development as multitargeted anticancer agents.