title: Previtamin D3 with a trans-fused decalin CD-ring has pronounced genomic activity.
abstract: Deletion of C19 in the structure of 1 alpha,25-dihydroxyvitamin D3 [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 D3 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.
authors.affiliation: Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Herestraat 49, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Verlinden
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
authors.forename: Christel
authors.initials: C
authors.lastname: Verboven
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.forename: Camiel
authors.initials: C
authors.lastname: De Ranter
authors.forename: Ling-Jie
authors.initials: LJ
authors.lastname: Gao
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Murad
authors.forename: Mihwa
authors.initials: M
authors.lastname: Choi
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.forename: Dirk
authors.initials: D
authors.lastname: Van Haver
authors.forename: Maurits
authors.initials: M
authors.lastname: Vandewalle
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: De Clercq
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
mesh_terms: D019943:Amino Acid Substitution; D000704:Analysis of Variance; D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008968:Molecular Conformation; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D047488:Retinoid X Receptors; D013329:Structure-Activity Relationship; D013552:Swine; D014157:Transcription Factors / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002762:Cholecalciferol; C025168:previtamin D(3)