Biological activity of CD-Ring modified 1 alpha,25-dihydroxyvitamin D Analogues: C-ring and five-membered D-Ring analogues

Nonsteroidal analogues of 1 alpha,25(OH)(2)D-3, lacking either the full fiv e-membered D ring (C-ring analogues) or the full six-membered C ring (D-rin g analogues) are more potent inhibitors of cell proliferation or inducers o f cell differentiation than is 1 alpha,25(OH)(2)D-3. Maximal superagonistic activity was seen for the C-ring analogue with a 24(R)-hydroxyl group in t he side chain [30- to 60-fold the activity of 1 alpha,25(OH)(2)D-3]. The 19 -nor-16-ene-26,27-bishomo C-ring analogue showed the best ratio of antiprol iferative to calcemic effects (1275-fold better than 1 alpha,25(OH)(2)D-3 a nd severalfold better than all vitamin D analogues so far described). The a nalogues are able to stimulate specific vitamin D-dependent genes and are a ctive in transfection assays using an osteocalcin promoter VDRE, Low bindin g affinity to the vitamin D binding protein, differences in metabolism, or affinity for the vitamin D receptor (VDR) are not the most important explan ations for the enhanced intrinsic activity. However, the analogues are able to induce conformational changes in the VDR, which makes the VDR-ligand co mplex more resistant against protease digestion than is 1 alpha,25(OH)(2)D- 3. In contrast to 20-epimer steroidal vitamin D analogues, 20-epimer C-ring analogues were less potent than analogues with a natural C-20 configuratio n. In conclusion, several nonsteroidal vitamin D analogues are superagonist s of 1 alpha,25(OH)(2)D-3 despite lower receptor affinity and, for the C-ri ng analogues, higher flexibility of the side chain; moreover, they have a b etter selectivity profile than all analogues yet published.