Synthesis Of19-Nor-Vitamin D Analogs

1α,25-dihydroxyvitamin D3(1,25-(OH)2VD3), the active metabolite of vitamin D3, is a major component in the regulation of calcium and phosphorous homeostasis.1,25-(OH)2VD3as well as its analogs have long been therapeutically used in patients with metabolic bone disease such as rickets. The formulation of the concept of vitamin D endocrine system was dependent upon the full understanding of the metabolism and mode of action of the active vitamin D. The universal presence of vitamin D receptor (VDR) in more than30tissues initiated consideration of possible functions of1,25-(OH)2VD3outside its classical role in calcium/bone homeostasis. These non-classical functions vary widely, but include control of cell proliferation and cell differentiation, and the synthesis and secretion of cytokines and other hormones. These actions suggest potential therapeutic applications of1,25-(OH)2VD3for cancer, immune modulation and regulation of endocrine systems. However, the high potency of1,25-(OH)2VD3to increase serum calcium and phosphate precludes its therapeutic application in most cases. Thus, much effort has been put to develop vitamin D analogs with greater selectivity. The19-nor-vitamin D analog, which was initially reported by DeLuca, showed promising dichotomy between cell differentiation and calcium regulation. Paricalcitol, a19-nor vitamin D analog bearing the side chain of vitamin D2, is now been widely used in the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease patients.In this paper, a new synthetic route of paricalcitol combined the method of organic synthesis and biotransformation was investigated. Firstly, vitamin D2was chemically modified, the thus obtained1α-OH-19-nor-vitamin D2was subjected to biotransformation which give paricalcitol in5%overall yield.It was also reported that24-homo-1,25-dihydroxyvitamin D3was selective both in vitro and in vivo. However,24-homo-19-nor-vitamin D analogs remain unreported until now. In this paper, a novel route of synthesis24-homo-19-nor-vitamin D analogs was developed. At first,1α-OH-19-nor-3,5-cyclo-vitamin D2was obtained through previous method of synthesis paricalcitol. Then, ozonolysis and coupling reaction were performed to allow the modification of side chain.1α-OH-22-dehydro-19-nor-vitamin D3was obtained in2.1%yield. This new route is effective in the synthesis of24-homo-19-nor-vitamin D analogs.