The Synthesis Of Doxercalciferol And Glycoside Analogues From Vitamin D₂

Vitamin D2, a common active form of vitamin D has been studied widely because of its metabolites in vivo playing a crucial role in calcium and phosphorus homeostasis. a large number of vitamin D2 analogues have been synthesized through the structure modification and most have been used to treat various diseases in clinical. Doxercalciferol is one of the examples with an significant effect on the chronic kidney disease. Glycosides found widely in natural products also have caused the chemists’attention due to a variety of biological activities.In this paper, Doxercalciferol was synthesized from vitamin D2 and the A ring of vitamin D2 was modified by a monosaccharide to obtain a series of vitamin D2 glycoside analogues. Moreover, the compounds were tested in the ability on antiproliferation. The main contents are as follows:(1) Optimal process conditions confirmed by our group were employed firstly to prepare the key intermediate 1.46 starting from vitamin D2. and then Doxercalciferol was abtained in total yield of 74.25% from the compound 1.46 being given photocatalytic double bond isomerization and removal protection of hydroxyl group.(2) The glycosidation reaction between vitamin D2 and two glycosyl donors, tetraacetate glucopyranosyl bromide and tetraacetate glucopyranosyl trichloroacetimidate, respectively was explored under the different catalysts. Ultimately a method for the glycosylation of vitamin D2 was determined and used in the glycosylation of fragment alcohol of vitamin D2 and a series of novel vitamin D2 glycoside analogues were synthesized and confirmed the structure by 1H NMR、13C NMR and HRMS or MS spectrums.(3) Based on the method of MTT, the four compounds (5.5,5.10,5.12a,5.12b) were tested on Hep G2 and MCF-7 cells respectively to find the antiproliferation activity to study the influence of the configuration and glycosyl of the compounds. All compounds (5.5,5.10, 5.12a,5.12b) exhibited good antiproliferation activities in vitro towards the two cells, the IC50 value of 5.12a is 77 nM which has the best inhibiting activity for MCF-7 cells.