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Molecules 2010, 15(3), 1590-1631; doi:10.3390/molecules15031590

Preparation of 16β-Estradiol Derivative Libraries as Bisubstrate Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 Using the Multidetachable Sulfamate Linker

Laboratory of Medicinal Chemistry, CHUQ (CHUL), Research Center and Laval University, Quebec, G1V 4G2, Canada
Author to whom correspondence should be addressed.
Received: 26 January 2010 / Revised: 8 February 2010 / Accepted: 3 March 2010 / Published: 10 March 2010
(This article belongs to the Special Issue Combinatorial Chemistry)
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Combinatorial chemistry is a powerful tool used to rapidly generate a large number of potentially biologically active compounds. In our goal to develop bisubstrate inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) that interact with both the substrate (estrone or estradiol) and the cofactor (NAD(P)H) binding sites, we used parallel solid-phase synthesis to prepare three libraries of 16β-estradiol derivatives with two or three levels of molecular diversity. From estrone, we first synthesized a sulfamate precursor that we loaded on trityl chloride resin using the efficient multidetachable sulfamate linker strategy recently developed in our laboratory. We then introduced molecular diversity [one or two amino acid(s) followed by a carboxylic acid] on steroid nucleus by Fmoc peptide chemistry. Finally, after a nucleophilic cleavage, libraries of 30, 63 and 25 estradiol derivatives were provided. A library of 30 sulfamoylated estradiol derivatives was also generated by acidic cleavage and its members were screened for inhibition of steroid sulfatase. Biological evaluation on homogenated HEK-293 cells overexpressing 17β-HSD1 of the estradiol derivatives carrying different oligoamide-type chains at C-16 first revealed that three levels of molecular diversity (a spacer of two amino acids) were necessary to interact with the adenosine part of the cofactor binding site. Second, the best inhibition was obtained when hydrophobic residues (phenylalanine) were used as building blocks.
Keywords: Solid-phase synthesis; sulfamate linker; steroid; inhibitor; 17β-HSD Solid-phase synthesis; sulfamate linker; steroid; inhibitor; 17β-HSD

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Bérubé, M.; Delagoutte, F.; Poirier, D. Preparation of 16β-Estradiol Derivative Libraries as Bisubstrate Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 Using the Multidetachable Sulfamate Linker. Molecules 2010, 15, 1590-1631.

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