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Design, Synthesis, Evaluation, and Structure of Vitamin D Analogues with Furan Side Chains
Author(s) -
Fraga Ramón,
Zacconi Flavia,
Sussman Fredy,
OrdóñezMorán Paloma,
Muñoz Alberto,
Huet Tiphaine,
Molnár Ferdinand,
Moras Dino,
Rochel Natacha,
Maestro Miguel,
Mouriño Antonio
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201102695
Subject(s) - side chain , furan , chemistry , side effect (computer science) , combinatorial chemistry , stereochemistry , computer science , organic chemistry , programming language , polymer
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.