Gill H S, Londowski J M, Corradino R A, Kumar R
Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905.
Steroids. 1986 Jul-Aug;48(1-2):93-108. doi: 10.1016/0039-128x(86)90044-9.
We synthesized 22-fluorovitamin D3 from (22S) cholest-5-ene-3 beta, 22-diol-3 beta-acetate 2. Compound 2 was treated with diethylaminosulfur trifluoride to give 22-fluorocholest-5-en-3 beta-acetate 3 and (E) 22-dehydrocholest-5-en-3 beta-acetate. Compound 3 was treated with N-bromosuccinimide to give a mixture of the respective 5,7- and 4,6-dienes. The 5,7-diene of 3 was separated from the 4,6-diene using the dienophile 4-phenyl-1,2,4-triazoline-3, 5-dione. 22-Fluoro-5 alpha,8 alpha-(3,5-dioxo-4-phenyl-1, 2,4-triazolino)-cholest-6-en-3 beta-acetate 4 was purified by flash chromatography and treated with lithium aluminum hydride to generate 22-fluorocholesta-5,7-dien-3 beta-ol 5. Photolysis of the diene 5, followed by thermal equilibration, resulted in the synthesis of 22-fluorovitamin D3 7. The vitamin 7 increased active intestinal calcium transport only at a dose of 50,000 pmol/rat, whereas vitamin D3 increased intestinal calcium transport at a dose of between 50 and 500 pmol/rat. 22-Fluorovitamin D3 7 did not mobilize bone and soft tissue calcium at a dose as high as 50,000 pmol/rat, whereas vitamin D3 was successful in doing so at a dose of 500 pmol/rat. When tested in the duodenal organ culture system, 22-fluorovitamin D3 7 had approximately 1/25th the potency of vitamin D3. It did not antagonize the activity of 1,25-dihydroxyvitamin D3. 22-Fluorovitamin D3 7 bound to the rat plasma vitamin D binding protein less avidly than vitamin D3. 22-Fluorovitamin D3 was bound very poorly to the chick intestinal cytosol receptor for 1,25-dihydroxyvitamin D3. We conclude that the introduction of fluorine at the C-22 position results in a vitamin D sterol with decreased biologic activity when compared to vitamin D3. The presence of a fluorine group at C-22 position inhibits the binding of the vitamin to rat vitamin D binding protein when compared to the binding of its hydrogen analog, vitamin D3.
我们从（22S）胆甾-5-烯-3β，22-二醇-3β-乙酸酯2合成了22-氟维生素D3。化合物2用二乙氨基三氟化硫处理，得到22-氟胆甾-5-烯-3β-乙酸酯3和（E）22-脱氢胆甾-5-烯-3β-乙酸酯。化合物3用N-溴代琥珀酰亚胺处理，得到相应的5,7-二烯和4,6-二烯的混合物。使用亲双烯体4-苯基-1,2,4-三唑啉-3,5-二酮从4,6-二烯中分离出3的5,7-二烯。22-氟-5α，8α-（3,5-二氧代-4-苯基-1,2,4-三唑啉）-胆甾-6-烯-3β-乙酸酯4通过快速柱色谱法纯化，并用氢化铝锂处理生成22-氟胆甾-5,7-二烯-3β-醇5。二烯5的光解，随后热平衡，导致22-氟维生素D3 7的合成。维生素7仅在剂量为50,000 pmol/大鼠时增加活性肠道钙转运，而维生素D3在剂量为50至500 pmol/大鼠时增加肠道钙转运。22-氟维生素D3 7在高达50,000 pmol/大鼠的剂量下不会动员骨和软组织中的钙，而维生素D3在500 pmol/大鼠的剂量下成功做到了这一点。在十二指肠器官培养系统中测试时，22-氟维生素D3 7的效力约为维生素D3的1/25。它不会拮抗1,25-二羟基维生素D3的活性。22-氟维生素D3 7与大鼠血浆维生素D结合蛋白的结合不如维生素D3紧密。22-氟维生素D3与鸡肠道细胞溶质中1,25-二羟基维生素D3的受体结合很差。我们得出结论，与维生素D3相比，在C-22位引入氟会导致维生素D甾醇的生物活性降低。与氢类似物维生素D3的结合相比，C-22位存在氟基团会抑制维生素与大鼠维生素D结合蛋白的结合。
