Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography (1095 views)
Mol Cancer Ther (ISSN: 1535-7163, 1538-8514electronic), 2008 Sep; 7(8): 2435-2444.
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Paper type: Journal Article,
Impact factor: 5.003, 5-year impact factor: 5.428
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-53349089862&partnerID=40&md5=4d4f3c49bf6a556109d89d26b4e5ea48
Keywords: 3 Hydroxy N 3, 3 Trifluoropropyl 16, 17 Seco Estra 1, 5(10) Triene 16, 17 Imide, 3 Sulfamoyloxy N 3, 667 Coumarin, Antineoplastic Agent, Estrone, Estrone 3 O Sulfamic Acid, Stx 64, Unclassified Drug, Animal Experiment, Animal Model, Antineoplastic Activity, Article, Binding Site, Breast Cancer, Controlled Study, Crystallization, Crystallography, Drug Synthesis, Female, Hydrogen Bond, Hydrophobicity, Molecular Model, Nonhuman, Priority Journal, Protein Interaction, Single Drug Dose, Chromatography, Liquid, X-Ray, Enzyme Inhibitors, Fluorine, Magnetic Resonance Spectroscopy, Protein Conformation, Wistar, Spectrometry, Electrospray Ionization, Steryl-Sulfatase, 5 (10) Triene 16,
Affiliations:
*** IBB - CNR ***
Department of Pharmacy and Pharmacology, Sterix Ltd., University of Bath, Bath, United Kingdom
Department of Endocrinology and Metabolic Medicine, Imperial College London, St. Mary's Hospital, London, United Kingdom
Istituto di Biostrutture e Bioimmagini-CNR, Naples, Italy
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Florence, Italy
Universit degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Florence, Italy
References:
Not available.
Mol Cancer Ther (ISSN: 1535-7163, 1538-8514electronic), 2008 Sep; 7(8): 2435-2444.
Export to BibTeX Export to EndNote
Paper type: Journal Article,
Impact factor: 5.003, 5-year impact factor: 5.428
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-53349089862&partnerID=40&md5=4d4f3c49bf6a556109d89d26b4e5ea48
Keywords: 3 Hydroxy N 3, 3 Trifluoropropyl 16, 17 Seco Estra 1, 5(10) Triene 16, 17 Imide, 3 Sulfamoyloxy N 3, 667 Coumarin, Antineoplastic Agent, Estrone, Estrone 3 O Sulfamic Acid, Stx 64, Unclassified Drug, Animal Experiment, Animal Model, Antineoplastic Activity, Article, Binding Site, Breast Cancer, Controlled Study, Crystallization, Crystallography, Drug Synthesis, Female, Hydrogen Bond, Hydrophobicity, Molecular Model, Nonhuman, Priority Journal, Protein Interaction, Single Drug Dose, Chromatography, Liquid, X-Ray, Enzyme Inhibitors, Fluorine, Magnetic Resonance Spectroscopy, Protein Conformation, Wistar, Spectrometry, Electrospray Ionization, Steryl-Sulfatase, 5 (10) Triene 16,
Affiliations:
*** IBB - CNR ***
Department of Pharmacy and Pharmacology, Sterix Ltd., University of Bath, Bath, United Kingdom
Department of Endocrinology and Metabolic Medicine, Imperial College London, St. Mary's Hospital, London, United Kingdom
Istituto di Biostrutture e Bioimmagini-CNR, Naples, Italy
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Florence, Italy
Universit degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Florence, Italy
References:
Not available.
Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography
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 (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 Nε2 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. Copyright © 2008 American Association for Cancer Research.
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 (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 Nε2 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. Copyright © 2008 American Association for Cancer Research.
Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography
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