Convergent synthesis of double point modified analogs of 1α,25-dihydroxyvitamin D₂ for biological evaluation

There is a long lasting controversy over the biological activity of vitamin D₂ as compared to vitamin D₃ 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 D₂, by a novel convergent strategy, to compare this compound directly with the activity of 1α,25-dihydroxyvitamin D₃. The same synthetic strategy also provided a series of (5E,7E) geometric isomers of the natural 1α,25-dihydroxyvitamin D₂ 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 ¹H and ¹³C 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 D2 still remains unknown. (5E,7E) modification in the structure of new analogs of 1α,25-dihydroxyvitamin D₂ is expected to give analogs with no influence on calcium level, as was previously obtained for the analogs of 1α,25-dihydroxyvitamin D₃. Investigation of the affinities for the vitamin D receptor and cell differentiation, transcriptional and calcium activities of the most active form of vitamin D₂ and of (5E,7E) analogs, compared to 1α,25-dihydroxyvitamin D₃, is underway in the collaborating laboratories.