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Lithocholic acid-based design of noncalcemic vitamin D receptor agonists.

Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, Avda das Ciencias s/n, 15782 Santiago de Compostela, Spain. Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, Avda das Ciencias s/n, 15782 Santiago de Compostela, Spain. Electronic address: antonio.mourino@usc.es. Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Herestraat 49, bus, 9802, 3000 Leuven, Belgium. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; Institut National de La Santé et de La Recherche Médicale (INSERM), U1258, 67400 Illkirch, France; Centre National de Recherche Scientifique (CNRS), UMR7104, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France; Institut National de La Santé et de La Recherche Médicale (INSERM), U1258, 67400 Illkirch, France; Centre National de Recherche Scientifique (CNRS), UMR7104, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France. Electronic address: rochel@igbmc.fr. Laboratory of Protein Biochemistry, Faculty of Biotechnology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland. Laboratory of Protein Biochemistry, Faculty of Biotechnology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland. Electronic address: ema@cs.uni.wroc.pl.

Bioorganic chemistry. 2021;:104878
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Abstract

The hypercalcemic effects of the hormone 1α,25-dihydroxyvitamin D3 (calcitriol) and most of known vitamin D metabolites and analogs call for the development of non secosteroidal vitamin D receptor (VDR) ligands as new selective and noncalcemic agonists for treatment of hyperproliferative diseases. We report on the in silico design and stereoselective synthesis of six lithocholic acid derivatives as well as on the calcemic activity of a potent LCA derivative and its crystallographic structure in complex with zVDR LBD. The low calcemic activity of this compound in comparison with the native hormone makes it of potential therapeutic value. Structure-function relationships provide the basis for the development of even more potent and selective lithocholic acid-based VDR ligands.