Aromatase inhibitors. Synthesis and evaluation of mammary tumor inhibiting activity of 3-alkylated 3-(4-aminophenyl)piperidine-2,6-diones.
Aromatase inhibitors. Synthesis and evaluation of mammary tumor inhibiting activity of 3-alkylated 3-(4-aminophenyl)piperidine-2,6-diones.
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芳香酶抑制剂。
DOI：
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发表时间：
1986
影响因子：
7.3
通讯作者：
C. Batzl
中科院分区：
文献类型：
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作者：
R. Hartmann;C. Batzl
报道了3-烷基取代的3-(4-氨基苯基)哌啶-2，6-二酮的合成和生物活性评价[H(1)，甲基(2)，乙基(3)，正丙基(4)，异丙基(5)，正丁基(6)，异丁基(7)，仲丁基(8)，正戊基(9)，异戊基(10)，2-甲基丁基(11)，仲戊基(12)，正己基(13)，正庚基(14)]。在体外，化合物4-14对人胎盘芳香化酶的抑制作用强于氨基谷氨酸亚胺(AG，化合物3)，后者最近被用于治疗激素依赖型乳腺癌。活性最强的衍生物化合物10的抑制率是AG的93倍。与AG相比，除5、7和8外，所有其他化合物对牛肾上腺脱氢酶的抑制作用相似或降低。与母体化合物相比，化合物4和6-12对孕马血清促性腺激素(PMSG)诱导的SD大鼠血浆雌二醇浓度有更强的抑制作用。化合物4、6-8、10和12对去卵巢9，10-二甲基-1，2-苯并茂(DMBA)荷瘤SD大鼠体内睾酮刺激的肿瘤生长抑制作用强于AG。作为比AG更强、更具选择性的雌激素生物合成抑制剂，一些新开发的AG衍生物可能是更好的治疗激素依赖型人类乳腺癌的候选药物。
The synthesis and biological evaluation of 3-alkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones as inhibitors of estrogen biosynthesis are described [H (1), methyl (2), ethyl (3), n-propyl (4), isopropyl (5), n-butyl (6), isobutyl (7), sec-butyl (8), n-pentyl (9), isopentyl (10), 2-methylbutyl (11), sec-pentyl (12), n-hexyl (13), n-heptyl (14)]. In vitro compounds 4-14 showed a stronger inhibition of human placental aromatase compared to aminoglutethimide (AG, compound 3), which recently has become used for the treatment of hormone-dependent breast cancer. The most active derivative, compound 10, showed a 93-fold stronger inhibition than AG. With the exception of 5, 7, and 8, all other compounds exhibited similar or decreased inhibition of bovine adrenal desmolase compared to AG. Compounds 4 and 6-12 showed a stronger inhibition of the plasma estradiol concentration of pregnant mare serum gonadotropin (PMSG) primed Sprague-Dawley (SD) rats compared to the parent compound. Compounds 4, 6-8, 10, and 12 inhibited the testosterone-stimulated tumor growth of ovariectomized 9,10-dimethyl-1,2-benzanthracene (DMBA) tumor-bearing SD rats more strongly than AG. Being stronger and more selective inhibitors of the estrogen biosynthesis than AG, some of the newly developed derivatives of AG might be better candidates for the treatment of the hormone-dependent human breast cancer.