Convergent synthesis of double point modified analogs of 1α,25-dihydroxyvitamin D for biological evaluation.

There is a long lasting controversy over the biological activity of vitamin D as compared to vitamin D in terms of maintaining of calcium homeostasis and raising the level of circulating 25-OH-D. To shed more light on this relationship we synthesized 1α,25-dihydroxyvitamin D, by a novel convergent strategy, to compare this compound directly with the activity of 1α,25-dihydroxyvitamin D. The same synthetic strategy also provided a series of (5E,7E) geometric isomers of the natural 1α,25-dihydroxyvitamin D as well as a series of double point modified analogs of its (24R)-epimer, including C-22 hydroxy derivatives. The structure of the new analogs was determined by H and C NMR as well as by mass spectrometry. The influence of (5E,7E) modification, alone or in combination with additional modifications in the side chain, on the activity profile and metabolic deactivation of analogs of 1α,25-dihydroxyvitamin D still remains unknown. (5E,7E) modification in the structure of new analogs of 1α,25-dihydroxyvitamin D is expected to give analogs with no influence on calcium level, as was previously obtained for the analogs of 1α,25-dihydroxyvitamin D. Investigation of the affinities for the vitamin D receptor and cell differentiation, transcriptional and calcium activities of the most active form of vitamin D and of (5E,7E) analogs, compared to 1α,25-dihydroxyvitamin D, is underway in the collaborating laboratories.