title: Aromatase inactivation by 2-substituted derivatives of the suicide substrate androsta-1,4-diene-3,17-dione.
abstract: To gain the structure-activity relationship of Delta(1)-androstenediones (Delta(1)-ADs) as mechanism-based inactivator of aromatase, series of 2-alkyl- and 2-alkoxy-substituted Delta(1)-ADs (6 and 9) as well as 2-bromo-Delta(1)-AD (14) were synthesized and tested. All of the inhibitors examined blocked aromatase in human placental microsomes in a competitive manner. In a series of 2-alkyl-Delta(1)-ADs (6), n-hexyl compound 6f was the most powerful inhibitor with an apparent K(i) value of 31 nM. The inhibitory activities of 2-alkoxy steroids 9 decreased in relation to length of the alkyl chain up to n-hexyloxy group (K(i): 95 nM for methoxy 9a). All of the alkyl steroids 6 along with the alkoxy steroid 9, except for the ethyl and n-propyl compounds 6b and 6c, caused a time-dependent inactivation of aromatase. The inactivation rates (k(inact): 0.020-0.084 min(-1)) were comparable to that of the parent compound Delta(1)-AD. The inactivation was prevented by the substrate AD, and no significant effect of l-cysteine on the inactivation was observed in each case. The results indicate that the 2-hexyl compound 6f act as the most powerful mechanism-based inactivator of aromatase among Delta(1)-AD analogs and may be submitted to the preclinical study in estrogen-dependent breast cancer.
authors.affiliation: Tohoku Pharmaceutical University, 4-1 Komatsushima-4-chome, Aobaku, Sendai 981-8558, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Takahashi
authors.forename: Wakako
authors.initials: W
authors.lastname: Handa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Umeta
authors.forename: Saki
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Kouwa
authors.initials: K
authors.lastname: Yamashita
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Numazawa
mesh_terms: D000730:Androstadienes / Q000737:chemistry / Q000494:pharmacology*; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta; D011247:Pregnancy; D013329:Structure-Activity Relationship
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; C006573:1,4-androstadiene-3,17-dione; D001141:Aromatase