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

46 Citations (Scopus)

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
StatePublished - 2000

Fingerprint

Dilatation and Curettage
Vitamin D
Calcitriol Receptors
Vitamin D-Binding Protein
Osteocalcin
Helper-Inducer T-Lymphocytes
Hydroxyl Radical
Transfection
Cell Differentiation
Digestion
Peptide Hydrolases
Cell Proliferation
Ligands
Genes

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.

Biological activity of CD-ring modified 1α,25-dihydroxyvitamin d analogues : C-ring and five-membered D-ring analogues. / Verstuyf, Annemieke; Verlinden, Lieve; Van Etten, Evelyne; Shi, Ling; Wu, Yusheng; D'Halleweyn, Chris; Van Haver, Dirk; Zhu, Gui Dong; Chen, Yong Jun; Zhou, Xiaoming; Haussler, Mark R; De Clercq, Pierre; Vandewalle, Maurits; Van Baelen, Hugo; Mathieu, Chantal; Bouillon, Roger.

In: Journal of Bone and Mineral Research, Vol. 15, No. 2, 2000, p. 237-252.

Research output: Contribution to journalArticle

Verstuyf, A, Verlinden, L, Van Etten, E, Shi, L, Wu, Y, D'Halleweyn, C, Van Haver, D, Zhu, GD, Chen, YJ, Zhou, X, Haussler, MR, 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, vol. 15, no. 2, pp. 237-252.
Verstuyf, Annemieke ; Verlinden, Lieve ; Van Etten, Evelyne ; Shi, Ling ; Wu, Yusheng ; D'Halleweyn, Chris ; Van Haver, Dirk ; Zhu, Gui Dong ; Chen, Yong Jun ; Zhou, Xiaoming ; Haussler, Mark R ; De Clercq, Pierre ; Vandewalle, Maurits ; Van Baelen, Hugo ; Mathieu, Chantal ; Bouillon, Roger. / Biological activity of CD-ring modified 1α,25-dihydroxyvitamin d analogues : C-ring and five-membered D-ring analogues. In: Journal of Bone and Mineral Research. 2000 ; Vol. 15, No. 2. pp. 237-252.
@article{4ef12ac5f7c64bd592758174ad4af87c,
title = "Biological activity of CD-ring modified 1α,25-dihydroxyvitamin d analogues: C-ring and five-membered D-ring analogues",
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.",
keywords = "Analogues, Differentiation, Modeling, Nonsteroidal, Proliferation, VDR conformation, Vitamin D",
author = "Annemieke Verstuyf and Lieve Verlinden and {Van Etten}, Evelyne and Ling Shi and Yusheng Wu and Chris D'Halleweyn and {Van Haver}, Dirk and Zhu, {Gui Dong} and Chen, {Yong Jun} and Xiaoming Zhou and Haussler, {Mark R} and {De Clercq}, Pierre and Maurits Vandewalle and {Van Baelen}, Hugo and Chantal Mathieu and Roger Bouillon",
year = "2000",
language = "English (US)",
volume = "15",
pages = "237--252",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Biological activity of CD-ring modified 1α,25-dihydroxyvitamin d analogues

T2 - C-ring and five-membered D-ring analogues

AU - Verstuyf, Annemieke

AU - Verlinden, Lieve

AU - Van Etten, Evelyne

AU - Shi, Ling

AU - Wu, Yusheng

AU - D'Halleweyn, Chris

AU - Van Haver, Dirk

AU - Zhu, Gui Dong

AU - Chen, Yong Jun

AU - Zhou, Xiaoming

AU - Haussler, Mark R

AU - De Clercq, Pierre

AU - Vandewalle, Maurits

AU - Van Baelen, Hugo

AU - Mathieu, Chantal

AU - Bouillon, Roger

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

KW - Analogues

KW - Differentiation

KW - Modeling

KW - Nonsteroidal

KW - Proliferation

KW - VDR conformation

KW - Vitamin D

UR - http://www.scopus.com/inward/record.url?scp=0033966244&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033966244&partnerID=8YFLogxK

M3 - Article

VL - 15

SP - 237

EP - 252

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 2

ER -