@article{ref1,
title="Aromatase inactivation by 2-substituted derivatives of the suicide substrate androsta-1,4-diene-3,17-dione",
journal="Journal of steroid biochemistry and molecular biology",
year="2009",
author="Takahashi, Madoka and Handa, Wakako and Umeta, Hiromi and Ishikawa, Saki and Yamashita, Kouwa and Numazawa, Mitsuteru",
volume="116",
number="3-5",
pages="191-199",
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.<p /><p>Language: en</p>",
language="en",
issn="0960-0760",
doi="10.1016/j.jsbmb.2009.05.015",
url="http://dx.doi.org/10.1016/j.jsbmb.2009.05.015"
}