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、化学 以及抗癌新药的生化性质和(3)检测 药物及其代谢物，以及潜在的生物调节剂和生物标志物 生物样品在体外和体内阐明药理和 测定其体内药代动力学。高性能液体 色谱分析是主要的分析方法。环戊烯基 胞嘧啶(CPE-C)，一种碳环核苷，其I期临床试验 因严重且不可预测的低血压而被停职，继续 在合作学习中。犬CPE-C输注的实验研究 血液动力学和药理学监测产生了一些相似之处 对患者的直立性低血压发作，以及生化和 这方面的药理学基础正在调查中。CPE-C的使用 用于脑瘤的原位递送也仍在考虑中， 由于CPE-C对人类具有显著的抗增殖作用 由5‘-三磷酸代谢物介导的体外胶质母细胞瘤 CPE-CTP。发展了一种快速的部分纯化方法。 人脱氧胞苷脱氨酶，抗癌的潜在靶点 毒剂，来自MOLT-4淋巴母细胞。这种酶已被用于鉴定 几种有效的新型脱氧嘧啶单磷酸类似物 抑制常数在纳摩尔范围内的竞争性抑制剂。 快速诊断的方法和适用参数的评价 比较了疏水性指数(logP、logk‘)的测定 液-液分配的计算机辅助计算 反相高效液相色谱法。所有的方法都提供了一个很好的，但不太完美的， 相关性。以聚合物为基础的柱上的反相高效液相色谱提供了 直接测定胞嘧啶对数P的最佳替代方法 具有潜在抗肿瘤活性的低亲脂性腺嘌呤核苷 活动。

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 orthostatic hypotensive episodes, and the biochemical and pharmacological basis of this is being investigated. The use of CPE-C for in situ delivery to brain tumors also remains under consideration, since CPE-C exerts a pronounced antiproliferative effect against human glioblastoma in vitro that is mediated by the 5'-triphosphate metabolite CPE-CTP. A rapid method has been developed for the partial purification of human deoxycytidylate deaminase, a potential target for anticancer agents, from MOLT-4 lymphoblasts. This enzyme has been used to identify several novel deoxypyrmidine monophosphate analogues as potent competitive inhibitors with inhibition constants in the nanomolar range. An evaluation of methods and appropiate parameters for the rapid determination of hydrophobicity indices (log P, log k') has compared computer-assisted calculation with liquid-liquid partitioning and reverse-phase HPLC. All methods provide a good, but less than perfect, correlation. Reverse-phase HPLC on a polymer-based column provides the best alternative to direct determination of log P for cytosine and adenine nucleosides of low lipophilicity with potential antitumor activity.