Synthesis and biological activities of 2α-chloro-1-epicalcitriol and 1-epicalcitriol

Anomalous diequatorial epoxide ring opening of 1β,2β-oxido-cholesta-5,7-diene-3β,25-diol 1 produces the 1β-hydroxy-2α-chloro-provitamin 2 and its corresponding 1β-hydroxy-provitamin 3. The provitamins 2 and 3 are transformed by irradiation and thermal isomerization to 2α-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 C3H10T 1 2 , and their effects were compared with those of the native vitamin D 3 derivatives 25(OH)D 3 and 1,25(OH) 2D 3. 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)D 3 has none affinity. The 2α-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 D 3 derivatives with extended serum half-life.