Synthesis, biological activity, and conformational analysis of CD-ring modified trans-decalin 1 alpha,25-dihydroxyvitamin D analogs.
A novel series of analogs of 1,25-dihydroxyvitamin D3, the hormonally active metabolite of vitamin D3, characterised by the presence of a trans-fused decalin CD-ring system, possesses surprising biological activities in combination with specific structural modifications in the flexible parts of the molecule, when compared with the natural hydrindane derivatives. (1) A large difference in biological activity is observed between the 20-epimeric trans-decalin analogs that follows a pattern opposite to what is usually observed for the natural ring size. (2) Several trans-decalin analogs that are modified in the seco-B-ring region, including previtamin derivatives, possess a pronounced vitamin D-like activity, whereas the corresponding hydrindane derivatives are inactive. The molecular origin of this behavior is still under study.
Chen
Yong-Jun
YJ
Laboratory for Organic Synthesis, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Gent, Belgium.
Gao
Ling-Jie
LJ
Murad
Ibrahim
I
Verstuyf
Annemieke
A
Verlinden
Lieve
L
Verboven
Christel
C
Bouillon
Roger
R
Viterbo
Davide
D
Milanesio
Marco
M
Van Haver
Dirk
D
Vandewalle
Maurits
M
De Clercq
Pierre J
PJ
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018922:HL-60 Cells; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D014809:Vitamin D-Binding Protein / Q000378:metabolism
D009281:Naphthalenes; D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; C007229:decalin; D002117:Calcitriol; D002118:Calcium