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

作者：Fraga Ramon; Zacconi Flavia; Sussman Fredy; Ordonez Moran Paloma; Munoz Alberto; Huet Tiphaine; Molnar Ferdinand; Moras Dino; Rochel Natacha; Maestro Miguel^*; Mourino Antonio

来源：Chemistry - A European Journal, 2012, 18(2): 603-612.

DOI：10.1002/chem.201102695

• cell adhesion
• furans
• gold
• synthesis design
• vitamin D analogues

Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1a,25-dihydroxy-vitamin D3 (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 (3?a, 3?b, 4?a, 4?b) 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 SuzukiMiyaura 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 3?a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.

• 出版日期2012-1