Development of Anti-Breast Cancer Agents Having Diverse Functions

点击翻译按钮获取中文摘要

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.