Design, Synthesis, Evaluation and Structure of Allenic 1α,25‐Dihydroxyvitamin D3 Analogs with Locked Mobility at C‐17

• Published in: Chemistry : a European journal Vol. 27; no. 53; pp. 13384 - 13389
• Main Authors: Fraga, Ramón, Len, Kateryna, Lutzing, Regis, Laverny, Gilles, Loureiro, Julian, Maestro, Miguel A., Rochel, Natacha, Rodriguez‐Borges, Enrique, Mouriño, Antonio
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 20.09.2021; John Wiley and Sons Inc
• Subjects: allenes; Analogs; Biological activity; Calciferol; Chain mobility; Chains; Chemistry; Cross coupling; Hypercalcemia; Immune system; Mobility; orthoester-Claisen rearrangement; Pd-catalyzed reactions; Receptors; synthesis; Vitamin D; vitamin D analogs; Vitamin D3
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202101578

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue‐selective new analogs. We have designed and synthesized the first examples of 1α,25‐dihydroxyvitamin D3 analogs bearing an allenic unit attached to the D ring to restrict the side‐chain conformational mobility. The triene system was constructed by a Pd0‐mediated cyclization/Suzuki‐Miyaura cross‐coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester‐Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)‐1α,25‐dihydroxy‐17,20‐dien‐24‐homo‐21‐nor‐vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side‐chain conformational requirements for biological activity. Looking for side‐chain conformational requirements of vitamin D analogs for selective biological activity, a new active vitamin D analog that has conformationally restricted mobility at the side chain and adopts a similar structure than the natural hormone 1α,25‐dihydroxyvitamin D3 in the binding pocket was designed by docking and synthesized. The highlights of the synthesis include a Pd0‐catalyzed cascade and an orthoester‐Claisen‐rearrangement for the formation of the trienic system and the allenic side‐chain, respectively.