Design, Synthesis, and Biological Studies of the A-Ring-Modified 1,25-Dihydroxyvitamin D3 Analogs
Antitumor effects of 1α,25-dihydroxyvitamin D3 analogs have recently become one of the major topics of the vitamin D research field. We focused on the structure-activity relationships of the A-ring moiety of the vitamin D molecule and found several strong agonists of the vitamin D receptor, using a design of introducing a functional group into the C2 position. In the first step, all eight possible diastereomers of novel 2-methyl-1,25-dihydroxyvitamin D3 were synthesized using the convergent method with palladium catalyzed coupling reaction. We studied conformational analysis of each isomer based on 1H NMR and computer calculations; and biologically, VDR binding affinity, potency of induction of HL-60 cell differentiation, and apoptosis were investigated in detail. The biological effect of double modification in a combination of the CD-ring side chain (20-epi, 20-epi-22R-methyl, and KH-1060 types) and the 2-methyl group was then evaluated. In this context, 5,6-trans derivatives of 2-methyl analogs were also synthesized and tested. Through these experiments, our accumulated knowledge that the 2α-methylated analog with the natural 1α,3β-dihydroxyl groups possesses a strong and unique biological profile guided us the next synthetic goal, i.e., three kinds of longer functional groups: 2a-alkyl, 2α-hydroxyalkyl, and 2α-hydroxyalkoxyl groups, which were introduced into 1α,25-dihydroxyvitamin D3, stereoselectively. We found that five of our new 2α-modified analogs show higher VDR-binding affinity than that of the natural hormone.
KeywordsPalladium Ph3P Polyol Dock Tert
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