Design, synthesis, and biological activity of D-bishomo-1α,25-dihydroxyvitamin D3 analogs and their crystal structures with the vitamin D nuclear receptor

• Published in: European journal of medicinal chemistry Vol. 271; p. 116403
• Main Authors: Fabisiak, Adrian, Brzeminski, Pawel, Sicinski, Rafal R., Rochel, Natacha, Maj, Ewa, Filip-Psurska, Beata, Wietrzyk, Joanna, Plum, Lori A., DeLuca, Hector F.
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 05-05-2024; Elsevier
• Subjects: 19-Norvitamin D; Calcemic activity; Cellular differentiation; Crystal structure; D-Bishomosteroids; Life Sciences; Vitamin D analogs; Vitamin D receptor; 19-Norvitamin D; VDR; Vitamin D receptor; Vitamin D analogs; D-Bishomosteroids; Calcemic activity; 1α,25-(OH)2D3; Cellular differentiation; Crystal structure
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116403

The biologically active metabolite of vitamin D3 - calcitriol – is a hormone involved in the regulation of calcium-phosphate homeostasis, immunological processes and cell differentiation, being therefore essential for the proper functioning of the human body. This suggests many applications of this steroid in the treatment of diseases such as rickets, psoriasis and some cancers. Unfortunately, using therapeutic doses of calcitriol is associated with high concentrations of this compound which causes hypercalcemia. For this reason, new calcitriol analogs are constantly sought, devoid of calcemic effects but maintaining its beneficial properties. In this study, we present the synthesis of vitamin D derivatives characterized by an enlarged (seven-membered) ring D. Preparation of the designed vitamin D compounds required separate syntheses of crucial building blocks (C/D-rings fragments with side chain and rings A) which were combined by different methods, including Wittig-Horner reaction and Suzuki coupling. Biological activities of the target vitamin D analogs were assessed both in vitro and in vivo, demonstrating their significant potency compared to the natural hormone. Furthermore, the successful crystallization of these compounds with the vitamin D receptor (VDR) enabled us to investigate additional molecular interactions with this protein.
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•First total synthesis of vitamin D3 analogs with 7-membered ring D.•X-ray crystal structures of zVDR LBD complexes of all synthesized analogs.•In vitro activity of all analogs in lung, breast and leukemia cell lines.•Synthesized analogs are active in stimulating calcium homeostasis in vivo.