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Research Articles: Therapeutics, Targets, and Development

Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography

¹ Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Bath, United Kingdom; ² Department of Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College London, Faculty of Medicine, St. Mary's Hospital, London, United Kingdom; ³ Istituto di Biostrutture e Bioimmagini-CNR, Naples, Italy; and ⁴ Università degli Studi di Firenze, Polo Scientifico,Laboratorio di Chimica Bioinorganica, Florence, Italy

Requests for reprints: Prof. Barry V.L. Potter, Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. Phone: 44-1225-386639; Fax: 44-1225-386114. E-mail: B.V.L.Potter{at}bath.ac.uk

Abstract

An improved steroid sulfatase inhibitor was prepared by replacing the N-propyl group of the second-generation steroid-like inhibitor (2) with a N-3,3,3-trifluoropropyl group to give (10). This compound is 5-fold more potent in vitro, completely inhibits rat liver steroid sulfatase activity after a single oral dose of 0.5 mg/kg, and exhibits a significantly longer duration of inhibition over (2). These biological properties are attributed to the increased lipophilicity and metabolic stability of (10) rendered by its trifluoropropyl group and also the potential H-bonding between its fluorine atom(s) and Arg⁹⁸ in the active site of human steroid sulfatase. Like other sulfamates, (10) is expected to be sequestered, and transported by, erythrocytes in vivo because it inhibits human carbonic anhydrase II (hCAII) potently (IC₅₀, 3 nmol/L). A congener (4), which possesses a N-(pyridin-3-ylmethyl) substituent, is even more active (IC₅₀, 0.1 nmol/L). To rationalize this, the hCAII-(4) adduct, obtained by cocrystallization, reveals not only the sulfamate group and the backbone of (4) interacting with the catalytic site and the associated hydrophobic pocket, respectively, but also the potential H-bonding between the N-(pyridin-3-ylmethyl) group and N₂ of Gln¹³⁶. Like (2), both (10) and its phenolic precursor (9) are non-estrogenic using a uterine weight gain assay. In summary, a highly potent, long-acting, and nonestrogenic steroid sulfatase inhibitor was designed with hCAII inhibitory properties that should positively influence in vivo behavior. Compound (10) and other related inhibitors of this structural class further expand the armory of steroid sulfatase inhibitors against hormone-dependent breast cancer. [Mol Cancer Ther 2008;7(8):2435–44]

Grant support: Sterix, a member of the Ipsen Group.

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.

Note: This article is dedicated to Dr. Melanie Trusselle (1973-2008).

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/14/08; revised 4/25/08; accepted 6/ 3/08.