Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: interaction with a mutant vitamin D receptor Arg274Leu

Vitamin D3 analogues have been developed for a mutant vitamin D receptor (VDR), Arg274Leu. The mutant VDR has a mutation at Arg274, which forms an important hydrogen bond with 1α-OH of 1α,25-dihydroxyvitamin D3 to anchor the ligand tightly in the VDR ligand binding pocket. Stereoselective synthesis of the A-ring part of the novel vitamin D analogue, 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D3 (4), from d-galactose was accomplished with the key steps of the introduction of the methyl and allyl groups to the chiral building blocks. The new analogue 4 is ca. 7.3-fold more active than the natural hormone 1α,25-dihydroxyvitamin D3 (1).

Stereoselective synthesis of the A-ring part of the novel vitamin D analogue of 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D3 from d-galactose for a mutant VDR (Arg274Leu) to rescue VDR binding affinity of the ligand is reported.