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

Molecular Cancer Therapeutics
L W Lawrence WooBarry V L Potter

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 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-ylme...Continue Reading

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Citations

Aug 12, 2014·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Dorota Bartusik, David Aebisher
Apr 23, 2013·Advanced Drug Delivery Reviews·Dorota Bartusik, Boguslaw Tomanek
Apr 5, 2011·Steroids·René Maltais, Donald Poirier
Mar 2, 2011·The Journal of Steroid Biochemistry and Molecular Biology·Jürgen GeislerAtul Purohit
Jan 18, 2011·Molecular and Cellular Endocrinology·L W Lawrence WooBarry V L Potter
Mar 15, 2016·European Journal of Medicinal Chemistry·Ramanpreet ShahNirmal Singh
Nov 10, 2012·Expert Opinion on Therapeutic Patents·Spencer J Williams
Feb 9, 2013·The Journal of Steroid Biochemistry and Molecular Biology·Yaser A Mostafa, Scott D Taylor
Jul 26, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·Giuseppina De SimoneVincenzo Alterio
Feb 13, 2010·Journal of Medicinal Chemistry·L W Lawrence WooBarry V L Potter
Dec 18, 2013·Chemical Reviews·William Spillane, Jean-Baptiste Malaubier
May 21, 2015·Journal of Medicinal Chemistry·Mark P Thomas, Barry V L Potter
Oct 16, 2018·ACS Omega·Dharshini GaneshapillaiBarry V L Potter

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