title: Probing the binding pocket of the active site of aromatase with 2-phenylaliphatic androsta-1,4-diene-3,17-dione steroids.
abstract: A series of 2-phenylaliphatic-substituted androsta-1,4-diene-3,17-diones (6) as well as their androstenedione derivatives (5) were synthesized as aromatase inhibitors to gain insights of structure-activity relationships of varying the alkyl moiety (C(1) to C(4)) of the 2-phenylaliphatic substituents as well as introducing a methyl- or trifluoromethyl function to p-position of a phenethyl moiety to the inhibitory activity. The inhibitors examined showed a competitive type inhibition. The 2-phenpropylandrosta-1,4-diene 6c was the most powerful inhibitor (K(i): 16.1nM) among them. Compounds 6c along with the phenethyl derivative 6b caused a time-dependent inactivation of aromatase (k(inact): 0.0293 and 0.0454min(-1) for 6b and 6c, respectively). The inactivation was prevented by the substrate androstenedione, and no significant effect of l-cysteine on the inactivation was observed in each case. Molecular docking of the phenpropyl compound 6c to aromatase was conducted to demonstrate that the phenpropyl group orients to a hydrophobic binding pocket in the active site to result in the formation of thermodynamically stable enzyme-inhibitor complex.
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: Kouwa
authors.initials: K
authors.lastname: Yamashita
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Numazawa
mesh_terms: D000730:Androstadienes / Q000737:chemistry / Q000494:pharmacology*; D000735:Androstenedione / Q000737:chemistry / Q000378:metabolism; D001141:Aromatase / Q000737:chemistry* / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D013379:Substrate Specificity / Q000187:drug effects; D013997:Time Factors
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; C006573:1,4-androstadiene-3,17-dione; D000735:Androstenedione; D001141:Aromatase