3TKC

Design, Synthesis, Evaluation and Structure of Vitamin D Analogues with Furan Side Chains

Summary for 3TKC

• Entry DOI: 10.2210/pdb3tkc/pdb
• Related: 3A3Z 3A40
• Descriptor: Vitamin D3 receptor, (1S,3R,5Z,7E,14beta,17alpha,20S)-20-[5-(1-hydroxy-1-methylethyl)furan-2-yl]-9,10-secopregna-5,7,10-triene-1,3-diol, SULFATE ION, ... (4 entities in total)
• Functional Keywords: alpha-helical sandwich, transcription, calcitriol, phosphorylation, nucleus
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P11473
• Total number of polymer chains: 1
• Total formula weight: 30024.61

Authors

Huet, T.,Moras, D.,Rochel, N. (deposition date: 2011-08-26, release date: 2012-03-07, Last modification date: 2023-09-13)

Primary citation

Fraga, R.,Zacconi, F.,Sussman, F.,Ordonez-Moran, P.,Munoz, A.,Huet, T.,Molnar, F.,Moras, D.,Rochel, N.,Maestro, M.,Mourino, A.
Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains.
Chemistry, 18:603-612, 2012

PubMed Abstract: Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1α,25-dihydroxy-vitamin D(3) (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3a, 3b, 4a, 4b) have now been developed. The triene system has been constructed by an efficient stereoselective intramolecular cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chemistry. These analogues exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of 3a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.

PubMed: 22162241
DOI: 10.1002/chem.201102695

Experimental method

X-RAY DIFFRACTION (1.75 Å)