CANCER CHEMOTHERAPY--NEW FOLATE ANALOGS

癌症化疗——新叶酸类似物

• 批准号: 2796262
• 负责人: MADHAVEN G NAIR
• 金额: $ 18.02万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2796262
• 关键词: HTC cell; aldehyde /ketone oxidoreductase; aminopterin; antineoplastics; athymic mouse; chemical structure function; dihydrofolate reductase; disease /disorder model; drug design /synthesis /production; drug metabolism; drug screening /evaluation; folate antagonist; high performance liquid chromatography; hydroxylation; laboratory mouse; leukemia; mass spectrometry; methotrexate analog; neoplasm /cancer chemotherapy; neoplastic cell; oxidoreductase inhibitor; polyglutamates; quinazolines

The long range objective of this research proposal is to develop anticancer drugs in the antifolate series that are very selective with low host toxicity. To achieve this objective, we propose to synthesize a series of antifolates that are: a) Synthetic substrates of dihydrofolate reductase (DHFR) that can be enzymatically activated to inhibitors of other folate based enzymes; b) Specific inhibitors of thymidylate synthase (TS), glycinamide- ribonucleotide formyltransferase (GARFTase), amino imidazole carboxamide ribonucleotide formyltransferase (AICARFTase), folylpolyglutamate synthetase (FPGS), and the nonpolyglutamatable counterparts of each of these enzyme inhibitors that are capable of facile transport to mammalian cells. Preferential accumulation of cytotoxic antifolate polyglutamates in tumors as a strategy for achieving selective toxicity in cancer chemotherapy will be investigated by exploiting the differential folylpolyglutamate hydrolase activity in tumor versus normal proliferative tissues. For this purpose, we propose to develop the required chemistry to deliver antifolate polyglutamates intact to mammalian cells via conjugation with macromolecules to cell cytosol subsequent to endocytosis. A Mass Spectral facility for the quantitative and qualitative analysis of folate and antifolate metabolites will be established at the University of South Alabama. All potential drugs will be evaluated thoroughly for their anticancer activity by our biological and industrial collaborators, using the appropriate biochemical and pharmacological test systems. Promising compounds will be evaluated in vivo for their antitumor activity in tumor bearing animals.

该研究计划的长期目标是开发抗癌药物 抗叶酸系列药物具有高选择性且宿主低 毒性。为了实现这一目标，我们建议综合一系列 抗叶酸剂是： a) 二氢叶酸还原酶的合成底物 (DHFR) 可被酶促激活为其他叶酸抑制剂 基于酶； b) 胸苷酸合酶（TS）的特异性抑制剂， 甘氨酰胺-核糖核苷酸甲酰基转移酶（GARFTase）、氨基咪唑 甲酰胺核糖核苷酸甲酰基转移酶（AICARFTase）， 叶酰聚谷氨酸合成酶 (FPGS) 和非聚谷氨酸 这些酶抑制剂的对应物能够轻松地 运输至哺乳动物细胞。 细胞毒性抗叶酸聚谷氨酸盐在肿瘤中优先积累 作为在癌症化疗中实现选择性毒性的策略将 通过利用差异叶酰聚谷氨酸水解酶进行研究 肿瘤与正常增殖组织中的活性。为此， 我们建议开发所需的化学物质来提供抗叶酸剂 通过与哺乳动物细胞缀合，聚谷氨酸保持完整 内吞作用后大分子进入细胞质。质谱 用于叶酸和叶酸的定量和定性分析的设施 南方大学将建立抗叶酸代谢产品 阿拉巴马州。所有潜在药物都将经过彻底评估 我们的生物和工业合作者的抗癌活性，使用 适当的生化和药理学测试系统。有前途 将在体内评估化合物在肿瘤中的抗肿瘤活性 承载动物。