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

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 1 alpha,25-dihydroxyvitamin D-3 analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd-0-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)-1 alpha,25-dihydroxy-17,20-dien-24-homo-21-nor-vitamin D-3 bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity.

Automated summary

The study focuses on the development of new vitamin D analogs with restricted side-chain mobility to address the hypercalcemic effects in therapeutic applications. By constructing the triene system and conducting reactions, the synthesis of target compounds was achieved and the biological activity in the binding domain of the vitamin D receptor was verified.