ANTITUMOR AND ANTIVIRAL NUCLEOSIDE ANALOGUES

抗肿瘤和抗病毒核苷类似物

• 批准号: 3170631
• 负责人: JIRI ZEMLICKA
• 金额: $ 25.8万
• 依托单位: BARBARA ANN KARMANOS CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1990-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3170631
• 关键词: adenosine; antineoplastics; antiviral agents; cytidine; drug design /synthesis /production; nucleoside analog

Novel nucleoside analogues will be prepared and studied as potential antitumor and antiviral agents. These compounds will include: (i) "Hydroxycarbocyclic" analogues of cytidine, 3- deazaadenosine, vidarabine and cytarabine, (ii) unsaturated carbocyclic nucleoside analogues related to neplanocin A including L-homocysteinylneplanocin A, (iii) phosphonate derivatives of open-chain unsaturated nucleoside analogues and (iv) analogues of adenosine deaminase inhibitor EHNA. All compounds will be obtained by chemical synthesis. Analogues (i) and (ii) will be obtained either in racemic form or optically pure by a new chemico-enzymatic approach. Antitumor activity and mechanism of action of the active analogues will be studied in vitro and in vivo in murine leukemia L 1210, P388, and sixteen solid tumor systems. Particular attention will be paid to: (i) inhibition of macromolecular synthesis, (ii) reversal studies with specific metabolites, (iii) alterations in nucleotide pool sizes, and (iv) effects on RNA maturation. Antiviral activity of the obtained analogues will also be investigated. Suitable analogues will be studied as substrates (inhibitors) of adenosine deaminase and adenosine homocysteine hydrolase.

新颖的核苷类似物将被准备并研究 潜在的抗肿瘤和抗病毒药物。 这些化合物会 包括：（i）胞丁的“羟基钙循环”类似物，3- Deazaadenosine，Vidarabine和Cytarabine，（ii）不饱和 碳循环核苷类似物与邻苯二型蛋白A相关 包括L-型囊藻蛋白酶A，（III）磷酸盐 开链不饱和核苷类似物和 （iv）腺苷脱氨酶抑制剂EHNA的类似物。 全部 化合物将通过化学合成获得。 类似物（i） （ii）将以消极的形式或光学纯正获得 通过一种新的化学酶方法。 抗肿瘤活性和活性的作用机理 类似物将在体外和体内研究鼠白血病L 1210，P388和16个实体瘤系统。 特别注意 将支付给：（i）抑制大分子合成，（ii） 具有特定代谢物的逆转研究，（iii）改变 核苷酸池大小，（iv）对RNA成熟的影响。 获得的类似物的抗病毒活性也将是 调查。 合适的类似物将作为基材（抑制剂）研究 腺苷脱氨酶和腺苷同型半胱氨酸水解酶。