Abstract
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.
Highlights
Introduction of molecular diversityN S O H O Rx id Ac age v a e clNu c cle leoph av ag ilic e H2 N S O RxSulfamate derivatives as prodrugs, inhibitors of steroid sulfatase and carbonic anhydrasePhenol derivatives as inhibitors of 17β-HSDs, ER antagonists and other therapeutic targets
The preparation of peptidosteroids was chosen since side chain of natural and non-natural amino acids provides an interesting pool of functionalities
Amino acid coupling procedures are well known for solid-phase synthesis and the Fmoc coupling strategy could be used with the sulfamate linker
Summary
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1), called human estradiol dehydrogenase [E.C.1.1.1.62], is a protein comprised of 327 amino acids that exists as a homodimer of 35 kDa [1]. An amine and/or a carboxylic acid as functional group to form interactions with the right part (adenosine) of the cofactor-binding site was added at the spacer end. The amine group on the adenosine moiety of 1a and the carboxylic acid function on 1b were found to be important for the interactions with the cofactor-binding site of this enzyme. Among the resins and the linkers known for preparing libraries of E2 derivatives by solid-phase chemistry [27] the linker sulfamate on trityl chloride resin developed by our research group was chosen [28,29] The chemical problems met during the preparation of library D will be discussed and solutions will be proposed
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