Estrogens are responsible for the growth of hormone-dependant breast cancer. Regulation of estrogen biosynthesis is considered as a potential therapeutic strategy for the control of breast cancer. The enzyme aromatase catalyzes conversion of androgens into estrogens in the last step of estrogen biosynthesis. Inhibition of aromatase is adopted as an efficient approach for the prevention and treatment of breast cancer. Many steroidal and nonsteroidal aromatase inhibitors have been developed and are used clinically for breast cancer therapy. In this report, it has been tried to incorporate some structural features (six membered lactam ring) of nonsteroidal aromatase inhibitors like aminoglutethimide and rogletimide into the A-/D-ring of the steroid nucleus with certain additional features responsible for binding to the enzyme aromatase. Some ring-A [17β-hydroxy-4-(4-substitutedphenyl)-4-aza-5-androsten-3-one] and ring-D modified steroidal compounds [4-substituted-17a-aza-D-homo-4-androstene-3,17-dione, 4-substituted-17-aza-Dhomo- 4-androstene-3,16,17a-trione, 4-substituted-17a-methyl-17a-aza-D-homo-4-androsten-3-one] were synthesized and screened for binding to the aromatase enzyme. None of the synthesized compounds showed promising aromatase inhibiting activity leading to the conclusion that structurally the original androstane ring skeleton should not be tampered with, for obtaining good aromatase inhibiting activity.
雌激素是激素依赖性乳腺癌生长的主要原因。
雌激素生物合成的调控已被认为是对乳腺癌进行控制的潜在治疗策略。芳香化酶是一种酶,它促进了雄激素转化为
雌激素,这是
雌激素生物合成的最后一步。因此,抑制芳香化酶成为预防和治疗乳腺癌的有效方法。现已开发出许多甾体和非甾体类芳香化酶
抑制剂,并用于临床乳腺癌治疗。在本报告中,我们试图将一些非甾体类芳香化酶
抑制剂(如
氨基
导眠能和洛格尔替酯)的结构特征(六元内酰胺环)引入甾体母核的A环和D环中,并加入一些能够与芳香化酶结合的结构特征。我们合成了一些A环[17β-羟基-4-(4-取代苯基)-4-氮杂-5-雄甾烯-3-酮]和D环修饰的甾体类化合物[4-取代-17α-氮杂-D-高-4-雄甾烯-3,17-二酮、4-取代-17-氮杂-D-高-4-雄甾烯-3,16,17α-三酮、4-取代-17α-甲基-17α-氮杂-D-高-4-雄甾烯-3-酮],并测试了它们与芳香化酶的结合能力。然而,合成的化合物均未显示出良好的芳香化酶抑制活性,这表明在结构上,原初的
雄甾烷环骨架不应被改动,以获得良好的芳香化酶抑制活性。