DESIGN OF NEW NUCLEOSIDES BASED ON ENZYME SPECIFICITIES

基于酶特异性的新核苷设计

• 批准号: 6102153
• 负责人: JOHN A SECRIST
• 金额: $ 30.5万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-11 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102153
• 关键词: alcohol phosphotransferase; antineoplastics; deoxycytidine; drug design /synthesis /production; enzyme inhibitors; nucleic acid chemical synthesis; nucleoside analog; nucleoside phosphate kinase; nucleoside ribosyltransferase; telomerase; telomere

The long-term goal of this project remains the development of new agents for the treatment of human cancers. Since most, if not all, of the nucleosides currently in use for the treatment of human cancers must phosphorylated to their active forms, we plan to investigate in some detail the enzymes that are known to carry out this activation. Deoxycytidine kinase is the primary, but not the only, enzyme that initiates this activation process, so we plan to focus on it, in collaboration with Dr. Donna S. Shewach of the University of michigan. We plan to prepare a broad series of compounds with a focus on them activating enzymes as well as their antitumor selectivity. We also plan to examine our collection of nucleoside triphosphates as inhibitors of telomerase, a DNA polymerase which is activated in human cancers. The studies will show triphosphates we have on hand or easily generate, and will provide us with SAR information that will be used in designing new compounds that will be more specific inhibitors for this enzyme, which appears to be an important new target for can chemotherapy.

该项目的长期目标仍然是开发新药剂 用于治疗人类癌症。 因为大多数（如果不是全部） 目前用于治疗人类癌症的核苷必须 磷酸化为其活性形式，我们计划进行一些详细研究 已知进行这种激活的酶。 脱氧胞苷 激酶是启动这一过程的主要酶，但不是唯一的酶 激活过程，因此我们计划与 Dr. 合作重点研究它。 密歇根大学的唐娜·S·谢瓦赫 (Donna S. Shewach)。 我们计划准备广泛的 系列化合物，重点关注它们激活酶以及 他们的抗肿瘤选择性。 我们还计划检查我们收集的三磷酸核苷 端粒酶抑制剂，端粒酶是一种在人体中被激活的 DNA 聚合酶 癌症。 研究将表明我们手头或容易拥有的三磷酸盐 生成并向我们提供 SAR 信息，这些信息将用于 设计新的化合物作为更具体的抑制剂 酶，这似乎是化疗的一个重要新靶点。