کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
9892108 1541100 2005 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structure-activity relationships of 2-, 4-, or 6-substituted estrogens as aromatase inhibitors
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Structure-activity relationships of 2-, 4-, or 6-substituted estrogens as aromatase inhibitors
چکیده انگلیسی
Aromatase, which is responsible for the conversion of androgens to estrogens, is a potential therapeutic target for the selective lowering of estrogen levels in patients with estrogen-dependent breast cancer. To develop a novel class of aromatase inhibitors, we tested series of 2- and 4-substituted (halogeno, methyl, formyl, methoxy, nitro, and amino) estrones (7 and 9), as well as series of 6α- and 6β-substituted (alkyl, phenalkyl, and alkoxy) estrones (13 and 14), and their estradiol analogs (8, 10, 11, and 12) as aromatase inhibitors. All of the inhibitors examined blocked the androstenedione aromatization in a competitive manner. Introduction of halogeno and methyl functions at C-2 of estrone as well as that of a phenalkyl or methyl function at the C-6α or C-6β position markedly increased affinity to aromatase (apparent Ki value = 0.10-0.66 μM for the inhibitors versus 2.5 μM for estrone). 6α-Phenylestrone (13c) was the most powerful inhibitor among the estrogens studied, and its affinity was comparable to that of the androgen substrate androstenedione. Estradiol analogs were much weaker inhibitors than the corresponding estrone compounds in each series, indicating that the 17-carbonyl group plays a critical role in the formation of a thermodynamically stable enzyme-inhibitor complex.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The Journal of Steroid Biochemistry and Molecular Biology - Volume 96, Issue 1, June 2005, Pages 51-58
نویسندگان
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