Synthesis and biological activities of 2 alpha-chloro-1-epicalcitriol and 1-epicalcitriol.
Anomalous diequatorial epoxide ring opening of 1 beta, 2 beta-oxido-cholesta-5,7-diene-3 beta, 25-diol 1 produces the 1 beta-hydroxy-2 alpha-chloro-provitamin 2 and its corresponding 1 beta-hydroxy-provitamin 3. The provitamins 2 and 3 are transformed by irradiation and thermal isomerization to 2 alpha-chloro-1-epicalcitriol NS3 (4) and 1-epicalcitriol NS8 (5), respectively. These two A-ring derivatives were tested for their in vitro biological activity in the mesenchymal, murine cell line C3H10T1/2, and their effects were compared with those of the native vitamin D3 derivatives 25(OH)D3 and 1.25(OH)2D3. NS3 and NS8 showed marked differences in their affinity for the vitamin D binding protein (DBP) and in their ability to inhibit cell proliferation. NS8 has the ability to bind to a high-affinity DBP-binding site for which 25(OH)D3 has none affinity. The 2 alpha-chloro-substitution (NS3) prevents binding to the postulated noncompetitive, NS8-specific DBP-binding site and diminishes the affinity to the vitamin D receptor (VDR) and therefore diminishing NS3's biological abilities. The elucidation of the structure-function relationships at the DBP-binding-sites could have major impact on the development of new vitamin D3 derivatives with extended serum half-life.
Schönecker
B
B
Department of Chemistry, Friedrich Schiller University Jena, Germany.
Reichenbächer
M
M
Gliesing
S
S
Gonschior
M
M
Griebenow
S
S
Scheddin
D
D
Mayer
H
H
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005347:Fibroblasts; D006801:Humans; D051379:Mice; D013237:Stereoisomerism
C110464:2-chloro-1-epicalcitriol; D002117:Calcitriol