THE ANALYTICAL CHEMISTRY OF NEW ANTICANCER DRUGS

本项目的目标是开发和应用 生物分析方法：(1)建立新的结构和纯度 抗肿瘤药物及其代谢物，(2)测定物理， 抗癌新药的化学和生化性质及(3) 测量药物、它们的代谢物和潜在的生物调节剂 生物样品中的生物标志物在体内外的阐明 药理和测定体内药代动力学。 高效液相色谱(HPLC)是主要的分析方法 接近。碳环核苷环戊烯基胞嘧啶(CPE-C) 其I期临床试验因严重和 不可预测的低血压，继续在合作研究中。CPE-C 血流动力学和药理学监测下的犬输液研究 与病人的低血压发作有一些相似之处， 这种现象的生化和药理学基础是 调查过了。合成了一种结构新颖的四氢吡喃吲哚。 确认为二氢罗特的一种抑制剂 脱氢酶(DHOD)--从头生成嘧啶所必需的酶 生物合成。这种新化合物的效力等于或等于 大于Brequina，一种DHOD抑制剂，是 研究中的抗肿瘤药物。一项比较疏水性的研究 由液-液分配确定的指数(LogP)和 胞嘧啶核苷和腺嘌呤核苷的反相高效液相色谱法(LOG K‘) 低亲脂性表现出良好的相关性，但不是很完美。 因此，使用高效液相色谱来估计分配系数 中极性到强极性的化合物不如直接极性化合物 用自行研制的微量摇瓶测定对数磷 方法。

The goal of this project is the development and application of bioanalytical methods to: (1) establish the structure and purity of new antitumor agents and their metabolites, (2) determine physical, chemical and biochemical properties of new anticancer drugs and (3) measure drugs, their metabolites, and potential biomodulators and biomarkers in biological samples to elucidate in vitro and in vivo pharmacology and to determine in vivo pharmacokinetics. High-performance liquid chromatography (HPLC) is the primary analytical approach. Cyclopentenyl cytosine (CPE-C), a carbocyclic nucleoside whose Phase I clinical trial was suspended because of severe and unpredictable hypotension, continues under collaborative study. CPE-C infusion studies in dogs with hemodynamic and pharmacologic monitoring have produced some similarities to patient hypotensive episodes, and the biochemical and pharmacological basis of this is being investigated. A tetrahydropyridoindole of novel structure has been identified and confirmed as an inhibitor of dihydroorotate dehydrogenase (DHOD), an enzyme required for de novo pyrimidine biosynthesis. This new compound possesses a potency equal to or greater than that of brequinar, a DHOD inhibitor that is an investigational antitumor agent. A study to compare hydrophobicity indices determined by liquid-liquid partitioning (log P) and reversed-phase HPLC (log k') for cytosine and adenine nucleosides of low lipophilicity showed a good, but less than perfect, correlation. Thus the use of HPLC to estimate the partition coefficients of moderately polar to very polar compounds is not as good as the direct determination of log P using our previously developed micro-shake flask method.