APHIDICOLIN: METABOLISM/SYNTHESIS OF ANTITUMOR AGENTS

这项拟议研究的目标是通过对其进行研究来促进 新陈代谢--一种特殊的DNA，在人类疾病中的作用 聚合酶α抑制剂和可能的抗肿瘤和抗病毒药物，以及 开发与结构相关的新的化疗药物 蜂王素。麦长管蚜已在 真核DNA聚合酶及其功能的鉴定 特定和独特的行动模式鼓励了临床试验。 然而，在抑制DNA合成的水平上，aphidicolin是 被大鼠、小鼠和小鼠的肝酶(S-9组分)快速“灭活” 大概是人类。由于失活的速度和巨大的 与异种生物有关的多种肝酶水平的变异性 代谢(由于性别、年龄和诱导)，蜂毒灵的代谢 可能会严重限制其在某些疾病州的就业。我们建议 一套完整的调查，通过它可以详细了解 将获得APHIDICIN代谢并将其应用于开发 合理定义APHIDICIN类似物和特定的酶抑制剂。 这些研究包括蚜菌素的代谢研究，它将 确定产生的代谢物的化学结构， 负责其在微粒体内(和胞浆)代谢的特定酶 从大鼠肝脏中分离出来，并对相关酶进行了诱导 化学制剂，包括除草剂。所有分离出的新化合物都将 检测DNA聚合酶α抑制活性。通过一种知识 代谢产物的结构及其对DNA聚合酶的抑制 活性，极大地改善了这一结构-活性关系 将获得唯一的化合物。此外，“活性”代谢物与 功能化网站(例如，饱和位置的羟化)可能有助于 在这种亲脂化合物的药物配方中。特异性抑制剂 参与新陈代谢的酶的作用(例如。抑制剂 特异性细胞色素P-450同工酶)，如果这样的抑制剂不能证明 致命的。一种对映体选择性的、直接的和多功能的合成进入 将开发能够合成的APHIPDICIN骨架 APHIDICOIN及其特定位点类似物的生成 修饰(旨在抑制酶生物转化)。

The goal of this proposed research is to promote through studies of its metabolism the utility in human disease of aphidicolin, a specific DNA polymerase Alpha inhibitor and possible antitumor and antiviral agent, and to develop new chemotherapeutic agents structurally related to aphidicolin. Aphidicolin has witnessed considerable application in identifying the functional roles of eukaryotic DNA polymerases and its specific and unique mode of action have encouraged clinical trials. However, aphidicolin, at levels active in inhibiting DNA synthesis, is rapidly "inactivated" by hepatic enzymes (S-9 fraction) of rats, mice and presumably humans. Due to the rate of inactivation and to the great variability in the levels of many liver enzymes involved in xenobiotic metabolism (due to sex, age and induction), the metabolism of aphidicolin could severely limit its employment in certain disease states. We propose an integrated set of investigations through which a detailed knowledge of aphidicolin metabolism will be obtained and applied to the development of rationally defined aphidicolin analogs and specific enzyme inhibitors. These investigations include metabolic studies of aphidicolin which will determine the chemical structures of the metabolites generated, the specific enzymes responsible for its metabolism in microsomes (and cytosol) isolated from rat liver, and the inducibility of the responsible enzymes by chemical agents including aphidicolin. All new compounds isolated will be assayed for DNA polymerase Alpha inhibitory activity. Through a knowledge of the structures of the metabolites and their DNA polymerase inhibition activities, vastly improved structure-activity relationships for this unique compund will be obtained. In addition, "active" metabolites with functionalized sites (eg. hydroxylation at saturated positions) may assist in the drug formulation of this lipophilic compound. Specific inhibitors of the enzymes involved in the metabolism will be pursued (eg. inhibitors of specific cytochrome P-450 isozymes), if such inhibitors would not prove lethal. An enantioselective, direct and versatile synthetic entry into the aphidicolin framework will be developed which is capable of synthesizing aphidicolin and generating aphidicolin analogs with specific site modifications (which are designed to inhibit enzymatic biotransformation).