C-GLYCOSYL ANTHRAQUINONES

拟议研究的长期目标是提供非 用于治疗红斑狼疮的毒性Pro-4-羟基酶抑制剂 与胶原蛋白过度产生相关的疾病：纤维症 肺肝、肝硬变、硬皮病，尤其是 与动脉粥样硬化和其他异常相关的情况 对循环系统的影响。目前还没有临床药物 在选择性抑制Pro-4-羟基酶的使用中，该酶 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 羟基酶抑制剂；一种简明而简单的方法 提出了这些化合物的制备方法。研究成果及 我们实验室开发的方法学将用于 短对映体全合成葡萄糖菌素B2，a 具有代表性的C-糖基安息香酚。类比也将是 为协作中的羟基酶抑制测试做准备 与詹姆斯·威勒森博士的团队(德克萨斯大学健康学院 达拉斯科学中心)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在这些方面被开发出来 实验室同时解决两个问题 C-糖基蒽醌类化合物的合成 糖衍生物上的芳香族芳香化反应 取代的蒽醌环和C-糖苷可以形成 只需一步。这使得非常快速地合成了 葡萄菌素及其类似物是可能的。

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.