Biological activity of CD-ring modified 1α,25-dihydroxyvitamin d analogues: C-ring and five-membered D-ring analogues

Annemieke Verstuyf, Lieve Verlinden, Evelyne Van Etten, Ling Shi, Yusheng Wu, Chris D'Halleweyn, Dirk Van Haver, Gui Dong Zhu, Yong Jun Chen, Xiaoming Zhou, Mark R Haussler, Pierre De Clercq, Maurits Vandewalle, Hugo Van Baelen, Chantal Mathieu, Roger Bouillon

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46 Scopus citations

Abstract

Nonsteroidal analogues of 1α,25(OH)2D3, lacking either the full five- membered D ring (C-ring analogues) or the full six-membered C ring (D-ring analogues) are more potent inhibitors of cell proliferation or inducers of cell differentiation than is 1α,25(OH)2D3. Maximal superagonistic activity was seen for the C-ring analogue with a 24(R)-hydroxyl group in the side chain [30- to 60-fold the activity of 1α,25(OH)2D3]. The 19-nor-16-ene- 26,27-bishomo C-ring analogue showed the best ratio of antiproliferative to calcemic effects (1275-fold better than 1α,25(OH)2D3 and severalfold better than all vitamin D analogues so far described). The analogues are able to stimulate specific vitamin D-dependent genes and are active in transfection assays using an osteocalcin promoter VDRE. Low binding affinity to the vitamin D binding protein, differences in metabolism, or affinity for the vitamin D receptor (VDR) are not the most important explanations for the enhanced intrinsic activity. However, the analogues are able to induce conformational changes in the VDR, which makes the VDR-ligand complex more resistant against protease digestion than is 1α,25(OH)2D3. In contrast to 20-epimer steroidal vitamin D analogues, 20-epimer C-ring analogues were less potent than analogues with a natural C-20 configuration. In conclusion, several nonsteroidal vitamin D analogues are superagonists of 1α,25(OH)2D3 despite lower receptor affinity and, for the C-ring analogues, higher flexibility of the side chain; moreover, they have a better selectivity profile than all analogues yet published.

Original languageEnglish (US)
Pages (from-to)237-252
Number of pages16
JournalJournal of Bone and Mineral Research
Volume15
Issue number2
Publication statusPublished - 2000

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Keywords

  • Analogues
  • Differentiation
  • Modeling
  • Nonsteroidal
  • Proliferation
  • VDR conformation
  • Vitamin D

ASJC Scopus subject areas

  • Surgery

Cite this

Verstuyf, A., Verlinden, L., Van Etten, E., Shi, L., Wu, Y., D'Halleweyn, C., ... Bouillon, R. (2000). Biological activity of CD-ring modified 1α,25-dihydroxyvitamin d analogues: C-ring and five-membered D-ring analogues. Journal of Bone and Mineral Research, 15(2), 237-252.