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 抗肿瘤剂及其代谢物，（2）测定物理， 新抗癌药物的化学和生物化学性质和（3） 测量药物、其代谢物和潜在的生物调节剂， 生物样品中的生物标志物，以阐明体外和体内 药理学和测定体内药代动力学。 高效液相色谱法（HPLC）是主要的分析方法， approach. 环戊烯基胞嘧啶（CPE-C），一种碳环核苷 其I期临床试验因严重和 不可预测的低血压，继续进行合作研究。 CPE-C 在犬中进行的输注研究，并进行血液动力学和药理学监测 已经产生了一些类似于病人的焦虑发作， 其生物化学和药理学基础 研究了一种结构新颖的四氢吡啶并吲哚， 鉴定并确认为二氢乳清酸盐抑制剂 脱氢酶（DHOD），一种从头嘧啶所需的酶 生物合成 这种新化合物的效力相当于或 比布喹那更大，一种DHOD抑制剂， 研究性抗肿瘤剂。 疏水性比较研究 通过液-液分配（log P）确定的指数， 胞嘧啶和腺嘌呤核苷的反相HPLC（log k '） 低亲脂性显示出良好但不完全的相关性。 因此，使用HPLC来估计分配系数 中等极性到极极性的化合物不如直接 使用我们先前开发的微型摇瓶测定log P 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.