7B39

Allene-Based Design of a Noncalcemic Vitamin D Receptor Agonist

Summary for 7B39

• Entry DOI: 10.2210/pdb7b39/pdb
• Descriptor: Vitamin D3 receptor A, Nuclear receptor coactivator 1, (1R,3S,Z)-5-(2-((3aS,7aS,E)-1-(6-hydroxy-6-methylhept-1-en-1-ylidene)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol, ... (5 entities in total)
• Functional Keywords: vitamin d receptor, gene regulation
• Biological source: Danio rerio (Zebrafish); More
• Total number of polymer chains: 2
• Total formula weight: 36308.39

Authors

Rochel, N. (deposition date: 2020-11-29, release date: 2021-09-01, Last modification date: 2024-01-31)

Primary citation

Fraga, R.,Len, K.,Lutzing, R.,Laverny, G.,Loureiro, J.,Maestro, M.A.,Rochel, N.,Rodriguez-Borges, E.,Mourino, A.
Design, Synthesis, Evaluation and Structure of Allenic 1 alpha ,25-Dihydroxyvitamin D 3 Analogs with Locked Mobility at C-17.
Chemistry, 27:13384-13389, 2021

PubMed Abstract: 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 D 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 -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 D bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity.

PubMed: 34224173
DOI: 10.1002/chem.202101578

Experimental method

X-RAY DIFFRACTION (2.13 Å)