The 16-ene vitamin D analogs

Numerous 16-ene vitamin D analogs were investigated as potential anticancer agents. Several structural modifications have been uncovered that contribute to the improvement in the stimulation of HL-60 cells differentiation, the inhibition of HL-60 cells proliferation and the reduction of calcemic properties in vivo. They include the introduction of 16-, 22E-, 23E- and 23Z-double bonds, 23-triple bond or 22R-allene, and substitution of C26 and C27-hydrogens with fluorine or methyl groups. The biggest gains have been achieved by combination of the 16-double bond with 23-double or triple bond and 26-trifluoro or 26,27-hexafluoro substitution patterns. Separately, the combination of the 16-double bond with 22R-allene has produced a highly active analog. In respect to modifications in the ring A, the high activities in cell differentiation and inhibition of cell proliferation with significant reduction of calcemic properties were observed in the Icc-fluoro, 3-desoxy, and 19-nor series. It was also shown that the lack of the la-hydroxy group can be overcome by an optimized modification in the ring D and the side chain; 25(OH)-16,23E-diene-26,27-F6D3 is fully active in HL-60 cell differentiation assay with only minimal effects on the cellular calcium homeostasis.