TY - JOUR
T1 - Previtamin D3 with a trans-fused decalin CD-ring has pronounced genomic activity
AU - Verlinden, Lieve
AU - Verstuyf, Annemieke
AU - Verboven, Christel
AU - Eelen, Guy
AU - De Ranter, Camiel
AU - Gao, Ling Jie
AU - Chen, Yong Jun
AU - Murad, Ibrahim
AU - Choi, Mihwa
AU - Yamamoto, Keiko
AU - Yamada, Sachiko
AU - Van Haver, Dirk
AU - Vandewalle, Maurits
AU - De Clercq, Pierre J.
AU - Bouillon, Roger
PY - 2003/9/12
Y1 - 2003/9/12
N2 - Deletion of C19 in the structure of 1α,25-dihydroxyvitamin D 3 [1,25(OH)2D3] does not substantially alter the biological potency but prevents the conversion between the vitamin and the previtamin form. Hence, this modification allows the study of locked previtamin and vitamin forms. The locked 19-nor-1,25(OH)2-previtamin D 3 analog (19-nor-previtamin D) had a low biological activity and was a rather weak activator of the genomic signal transduction pathway. 19-Nor-trans-decalin-1,25(OH)2-vitamin D3 (19-nor-TD-vitamin D), characterized by the presence of a trans-fused decalin CD-ring system, was 10-fold more potent than the parent compound and was a potent activator of the genomic signal transduction pathway. Surprisingly, the previtamin, 19-nor-trans-decalin-1,25(OH)2-previtamin D3 (19-nor-TD-previtamin D), was as potent as 1,25(OH)2D3 in inhibiting cell proliferation and inducing cell differentiation and represents the first previtamin structure with pronounced vitamin D-like activity. Furthermore, this compound interacted as efficiently as 1,25(OH) 2D3 with the vitamin D receptor (VDR), retinoid X receptor (RXR), coactivators, and DNA, which illustrated its potent ability to activate the genomic signal transduction pathway. Analysis of the transactivation potency of 12 VDR point mutants after stimulation with 19-nor-TD-previtamin D revealed that this analog used the same contact points within the receptor as did 1,25(OH)2D3. This could be confirmed by modeling analysis of this compound in the ligand binding pocket of VDR. In conclusion, a previtamin D3 analog is presented with genomic activities equivalent to 1,25(OH)2D3.
AB - Deletion of C19 in the structure of 1α,25-dihydroxyvitamin D 3 [1,25(OH)2D3] does not substantially alter the biological potency but prevents the conversion between the vitamin and the previtamin form. Hence, this modification allows the study of locked previtamin and vitamin forms. The locked 19-nor-1,25(OH)2-previtamin D 3 analog (19-nor-previtamin D) had a low biological activity and was a rather weak activator of the genomic signal transduction pathway. 19-Nor-trans-decalin-1,25(OH)2-vitamin D3 (19-nor-TD-vitamin D), characterized by the presence of a trans-fused decalin CD-ring system, was 10-fold more potent than the parent compound and was a potent activator of the genomic signal transduction pathway. Surprisingly, the previtamin, 19-nor-trans-decalin-1,25(OH)2-previtamin D3 (19-nor-TD-previtamin D), was as potent as 1,25(OH)2D3 in inhibiting cell proliferation and inducing cell differentiation and represents the first previtamin structure with pronounced vitamin D-like activity. Furthermore, this compound interacted as efficiently as 1,25(OH) 2D3 with the vitamin D receptor (VDR), retinoid X receptor (RXR), coactivators, and DNA, which illustrated its potent ability to activate the genomic signal transduction pathway. Analysis of the transactivation potency of 12 VDR point mutants after stimulation with 19-nor-TD-previtamin D revealed that this analog used the same contact points within the receptor as did 1,25(OH)2D3. This could be confirmed by modeling analysis of this compound in the ligand binding pocket of VDR. In conclusion, a previtamin D3 analog is presented with genomic activities equivalent to 1,25(OH)2D3.
UR - http://www.scopus.com/inward/record.url?scp=0042818000&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0042818000&partnerID=8YFLogxK
U2 - 10.1074/jbc.M302045200
DO - 10.1074/jbc.M302045200
M3 - Article
C2 - 12829710
AN - SCOPUS:0042818000
SN - 0021-9258
VL - 278
SP - 35476
EP - 35482
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -