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Development of Anti-Breast Cancer Agents Having Diverse Functions

具有多种功能的抗乳腺癌药物的开发

基本信息

批准号：
12672156
负责人：
NUMAZAWA Mitsuteru
金额：
$ 1.92万
依托单位：
Tohoku Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

We initially carried out studies to further elucidate the structure-activity relationship of aromatase inhibitor as well as the catalytic function of aromatase. Then, based on these findings, agents having two functions, aromatase inhibitory activity and estrogen sulfatase inhibitory activity, were synthesized and tested their biological activities. The results were summarized as follows.1. Structure-activity relationship and aromatase reaction of 19-oxygenated 6-methylandrostenediones and 6-alkoxy- and 6-acyloxy androstenediones revealed that there would be two binding sites in aromatase and steric and stereo electronic effects would play an important role in the binding.2. New insights into the aromatization mechanism were obtained using 4β, 5β-epoxy androstenediones as substrates.3. Two binding sites theory was further confirmed using 16α-hydroxylated androgens as substrate of aromatase.4. It is proven that a hydrophilic interaction of an aromatase inhibitor with the binding site is involved in the binding of 3-deoxy steroids.5. Based on the above results, we employed 6-phenyl-substituted androstenedione analogs as molecules having the diverse functions. The phenyl moiety was converted into p-sulfamoyl group to exert the sulfatase inhibitory activity. Compounds synthesized have good aromatase inhibitory activity but poor sulfatase inhibitory activity.

为了进一步阐明芳香化酶抑制剂的构效关系以及芳香化酶的催化功能，我们进行了初步的研究。在此基础上，合成了具有芳香化酶抑制活性和雌激素硫酸酯酶抑制活性两种功能的制剂，并对其生物活性进行了测试。结果总结如下：1。19-氧合6-甲基雄烯二酮与6-烷氧基和6-酰基雄烯二酮的构效关系和芳香化酶反应表明，芳香化酶中存在两个结合位点，立体电子效应和立体电子效应在其结合中起重要作用。以4β， 5β-环氧雄烯二酮为底物，对其芳构化机理有了新的认识。利用16α-羟基化雄激素作为芳香化酶底物，进一步证实了双结合位点理论。已经证明芳香化酶抑制剂与结合位点的亲水性相互作用参与了3-脱氧类固醇的结合。基于以上结果，我们采用6-苯基取代雄烯二酮类似物作为具有不同功能的分子。苯基部分转化为对磺胺酰基，发挥磺胺酶抑制活性。合成的化合物具有良好的芳香酶抑制活性，但较差的硫酸盐酶抑制活性。