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

Research output: Contribution to journalArticle

47 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
DOIs
StatePublished - 2000

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Verstuyf, A., Verlinden, L., Van Etten, E., Shi, L., Wu, Y., D'Halleweyn, C., Van Haver, D., Zhu, G. D., Chen, Y. J., Zhou, X., Haussler, M. R., De Clercq, P., Vandewalle, M., Van Baelen, H., Mathieu, 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. https://doi.org/10.1359/jbmr.2000.15.2.237