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J. Biol. Chem., Vol. 279, Issue 46, 48071-48078, November 12, 2004

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Biochemical and Biological Characterization of a Novel Anti-aromatase Coumarin Derivative^*

Shiuan Chen, Michael Cho, Kimberly Karlsberg, Dujin Zhou, and Yate-Ching Yuan

From the Department of Surgical Research and Division of Informational Sciences, Beckman Research Institute of the City of Hope, Duarte, California 91010

Estrogen stimulates the proliferation of estrogen receptor (ER)-positive breast cancer cells. Aromatase is the enzyme responsible for the conversion of androgens into estrogens, and synthetic aromatase inhibitors such as letrozole, anastrozole, and exemestane have proven to be effective endocrine regimens for ER-positive breast cancer. In a recent study, we have found that 4-benzyl-3-(4'-chlorophenyl)-7-methoxycoumarin is a potent competitive inhibitor of aromatase with respect to the androgen substrate. Its K_i value was determined to be 84 nM, significantly more potent than several known aromatase inhibitors. The specific interaction of this compound with aromatase was further demonstrated by the reduction of its binding by several mutations at the active site region of aromatase and evaluated by computer modeling analysis. The structure-activity studies have revealed that three functional groups (i.e. 3-(4'-chlorophenyl), 4-benzyl, and 7-methoxyl) of this coumarin are important in its inhibition of aromatase. In addition, through a matrigel thread three-dimensional cell culture, this compound was shown to behave like known aromatase inhibitors that suppress the proliferation of aromatase and estrogen receptor positive MCF-7aro breast cancer cells. This coumarin has been shown not to be cytotoxic at up to 40 µM. It was found not to be an inhibitor of steroid 5-reductase that also utilizes androgen as the substrate and not to be a ligand of ER, ER, estrogen-related receptors, or androgen receptor. These results demonstrate that coumarins (a common type of phytochemical) or their derivatives can be potent inhibitors of aromatase and may be useful in suppressing aromataseand ER-positive breast tumors.

Received for publication, June 18, 2004 , and in revised form, September 2, 2004.

^* This research was supported by National Institutes of Health Grants ES08258 and CA44735. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 626-359-8111 (ext. 63454); Fax: 626-301-8972; E-mail: schen{at}coh.org.

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