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

• Published in: Molecular cancer therapeutics Vol. 7; no. 8; pp. 2435 - 2444
• Main Authors: Woo, L W Lawrence, Fischer, Delphine S, Sharland, Christopher M, Trusselle, Melanie, Foster, Paul A, Chander, Surinder K, Di Fiore, Anna, Supuran, Claudiu T, De Simone, Giuseppina, Purohit, Atul, Reed, Michael J, Potter, Barry V L
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-08-2008
• Subjects: Animals; Antineoplastic Agents - pharmacology; Chromatography, Liquid; Crystallography, X-Ray; Enzyme Inhibitors - pharmacology; Female; Fluorine - chemistry; hormone-dependent breast cancer; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Protein Conformation; Rats; Rats, Wistar; Spectrometry, Mass, Electrospray Ionization; steroid sulfatase inhibitors; Steryl-Sulfatase - antagonists & inhibitors; Steryl-Sulfatase - chemistry
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0195

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 Arg 98 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 (IC 50 , 3 nmol/L). A congener ( 4 ), which possesses a N -(pyridin-3-ylmethyl) substituent, is even more active (IC 50 , 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 Nε 2 of Gln 136 . 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]