3,17-disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol derivatives: Synthesis, in vitro and in vivo anticancer activity
3,17-disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol derivatives: Synthesis, in vitro and in vivo anticancer activity
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DOI：
10.1021/jm070405v
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发表时间：
2007-09-06
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：
Bubert, Christian;Leese, Mathew P.;Potter, Barry V. L.
雌二醇-3,17- o， o -双磺胺酸酯抑制类固醇磺胺酶（STS），碳酸酐酶（CA），当取代在C-2时，癌细胞增殖和血管生成。探索了雌二醇-3,17- o， o -双氨基磺酸盐的C-2替代和17-氨基磺酸盐替代，并开发了高效实用的合成方法。对人类癌细胞的活性评价表明，2-甲基衍生物27 （DU145 GI(50) = 0.38, μ M）是其系列中活性最高的，而2-乙基-17-氨基甲酸酯衍生物52 （GI(50) = 0.22 μ M）是其系列中活性最高的（比较2-乙二醇-3,17- o， o -双氨基甲酸酯4 GI(50) = 0.21 μ M）。较大的C-2取代基对活性有害。通过x射线晶体学研究了2-甲氧基-17-氨基甲酸酯50，与母体双氨基磺酸盐3相比，其STS抑制剂的强度弱了13倍。4作为口服抗肿瘤药物的潜力在乳腺癌和前列腺癌异种移植中得到证实。在MDA-MB-231模型中，观察到肿瘤生长或消退的显著减少，并且在停止治疗后效果持续。3- o -磺胺酰化2-烷基戊二醇-17- o -氨基甲酸酯和氨基甲酸酯具有相当大的抗癌潜力。
Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI(50) = 0.38,mu M) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI(50) = 0.22 mu M) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI(50) = 0.21 mu M). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents.