SYNTHESIS AND EVALUATION OF 1,25-(OH)2-D3 GLYCOSIDES

1，25-二羟基维生素D3及其类似物已被证明可用作 用于多种疾病的药物。活性维生素D3 已经显示出有效地维持骨矿物质密度， 降低患有骨质疏松症的老年妇女的骨折率 吃这种药 然而，这种药物尚未获得广泛接受 由于其引起钙毒性的巨大潜力， 包括高钙尿症、高钙血症、肾结石和软组织 钙化 这种担忧的部分原因是，1，25（OH）2D 3 是维生素D的生物活性形式，口服时具有 直接作用于小肠，提高效率， 钙吸收1，25（OH）2D 3也被证明是 非常有效的口服和局部治疗 银屑病 然而，由于1，25（OH）2D 3是脂溶性化合物，其 局部制剂是困难的并且通常需要基于 准备. 油腻的软膏制剂不太容易被 病人比奶油为基础。1，25（OH）2D，3，口服时， 直接与小肠相互作用，以提高效率 钙吸收 所需要的是一种形式的1，25（OH）2D 3，其处于 前药形式，使得当口服时，其不具有第一前药形式， 通过对肠道的生物效应。 此外，如果前药形式 1，25（OH）_2D_3的水溶性增加，可以配制成 一种治疗牛皮癣的乳膏。 这种可行性的目标是 第一阶段的建议是化学合成两个糖苷衍生物， 1，25（OH）2D 3，包括1，25（OH）2D 3 - 3 β-葡糖苷，和 1，25（OH）2D 3-麦芽糖苷。 一旦这些化合物被合成， 水溶性将与它们的生物活性一起沿着进行研究 体外

1,25-Dihydroxyvitamin D3 and its analogs have proven to be useful as pharmacologic agents for a variety of diseases. 1,25-Dihydroxyvitamin D3 has been shown to be effective in maintaining bone mineral density and decreasing fracture rate in elderly women who suffer from osteoporosis and take this drug. However, this drug has not gained wide acceptance world wide because of its great potential of causing calcium toxicity including hypercalciuria, hypercalcemia, kidney stones and soft tissue calcification. Part of the reason for this concern, is that 1,25(OH)2D3 is the biologically active form of vitamin D and when given orally has a direct action on the small intestine by increasing the efficiency of calcium absorption. 1,25(OH)2D3 has also been demonstrated to be extremely effective both orally and topically for the treatment of psoriasis. However, since 1,25(OH)2D3 is a lipid soluble compound, its topical formulation is difficult and often requires an ointment based preparation. Greasy ointment preparations are less acceptable to patients than cream based ones. 1,25(OH)2D,3, when given orally, interacts directly with the small intestine to raise the efficiency of calcium absorption. What is needed is a form of 1,25(OH)2D3 that is in a prodrug form so that when it is taken orally it does not have a first pass biologic effect on the intestine. In addition, if the prodrug form of 1,25(OH)2D3 had increased water solubility, it could be formulated in a cream for the treatment of psoriasis. The goal of this feasibility phase I proposal is to chemically synthesize two glycoside derivatives of 1,25(OH)2D3 including 1,25(OH)2D3 -3beta-glucoside, and 1,25(OH)2D3-maltoside. Once these compounds have been synthesized, their water solubility will be investigated along with their biologic activity in vitro.