C-GLYCOSYL ANTHRAQUINONES

这项研究的长期目标是提供非 毒性脯氨酰-4-羟化酶抑制剂用于治疗 与胶原蛋白过度生成相关的疾病：纤维化 肺和肝，肝硬化，硬皮病，特别是 与动脉粥样硬化和其他异常相关的病症 的循环系统。 目前还没有临床药物 在选择性抑制脯氨酰-4-羟化酶的应用中，酶 负责胶原蛋白生物合成的速率决定步骤。 某些C-糖基蒽醌天然产物是有效的 羟化酶抑制剂; 提出了这些化合物的制备方法。 研究成果和 我们实验室开发的方法将用于 一种短的对映体特异性的全合成vineomycinone B2， 代表性的C-糖基蒽醌。 类似物也将 准备用于羟化酶抑制试验 与詹姆斯·威尔森博士的小组（德克萨斯大学健康 科学中心，达拉斯）和该部门的细胞毒性， 与格雷戈里·帕特森博士合作。 新的，非常有效的方法已经开发出来， 实验室，同时解决这两个问题所提出的 C-糖基蒽醌的合成： 在糖衍生物上的芳族缩合反应， 取代的蒽醌环和C-糖苷可以形成 在一个单一的步骤。 这使得一个非常迅速的综合， 可能的是vineomycins及其类似物。

The long-term goal of the proposed research is to provide non- toxic prolyl-4-hydroxylase inhibitors for use in the treatment of diseases associated with the overproduction of collagen: fibroses of lung and liver, hepatic cirrhosis, scleroderma and especially conditions associated with atherosclerosis and other abnormalities of the circulatory system. There are currently no clinical agents in use which selectively inhibit prolyl-4-hydroxylase, the enzyme responsible for the rate-determining step of collagen biosynthesis. Certain C-glycosyl anthraquinone natural products are potent hydroxylase inhibitors; a concise and simple methodology for the preparation of these compounds is proposed. Research results and methodology which has been developed in our lab will be used for a short enantiospecific total synthesis of vineomycinone B2, a representative C-glycosyl anthraquinone. Analogs will also be prepared for testing for hydroxylase inhibition in collaboration with Dr. James Willerson's group (University of Texas Health Science Center, Dallas) and for cytotoxicity in this Department in collaboration with Dr. Gregory Patterson. New, very efficient methods have been developed in these laboratories to simultaneously solve both problems posed by the synthesis of C-glycosyl anthraquinones: by performing an aromatic annelation reaction on a sugar derivative, the substituted anthraquinone ring and the C-glycoside can be formed in a single step. This makes an extremely expeditious synthesis of the vineomycins and their analogs possible.