Vitamin D: concerning the relationship between molecular topology and biological function.

Structure-function relationships for vitamin D, its metabolites, and analogs are discussed with particular emphasis on the A-ring conformation. It is emphasized that the A-ring of these seco-steroids consists of a pair of rapidly equilibrating chair conformers. As a consequence, different chair conformations produce different orientations of substituent groups in the A-ring. It is proposed that the 1alpha-hydroxyl of 1alpha,25-dihydroxyvitamin D(3) or its geometric equivalent in analogs must occupy the equatorial, as opposed to the axial, orientation for optimization of biological activity. This proposal is discussed in relation to existing published data on structure-function relationships and the steroid hormone model of action for the biologically active form of vitamin D. This three-dimensional topological model suggests the synthesis of other vitamin D analogs.