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

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Fraga, Ramón | Zacconi, Flavia | Sussman, Fredy | Ordóñez-Morán, Paloma | Muñoz, Alberto | Huet, Tiphaine | Molnár, Ferdinand | Moras, Dino | Rochel, Natacha | Maestro, Miguel | Mouriño, Antonio

Edité par CCSD ; Wiley-VCH Verlag -

International audience. 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 ( 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 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 3 a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.

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