CYCLIC NUCLEOTIDES, CYCLOPHOSPHAMIDES, AND ANTIVIRALS

环核苷酸、环磷酰胺和抗病毒药

• 批准号: 3163437
• 负责人: WESLEY G BENTRUDE
• 金额: $ 21.03万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1975
• 资助国家: 美国
• 起止时间: 1975-06-01 至 1994-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3163437
• 关键词: Dictyostelium; X ray crystallography; acyclovir; antineoplastics; antiviral agents; chemical carcinogenesis; chemical models; conformation; cyclic AMP; cyclic GMP; cyclic nucleoside monophosphate; cyclophosphamide; dinucleotide; drug design /synthesis /production; drug resistance; drug screening /evaluation; herpes simplex virus 1; nuclear magnetic resonance spectroscopy; phosphamide; phosphates; phosphites; phosphodiesterases; phosphonate; phosphorus; protein kinase; radiotracer; thymidylate synthase

Research is proposed in four diverse but related areas. One long range goal is a better understanding of the role of cyclic nucleotides (cAMP in particular and also cGMP) in cell proliferation and maligant transformation through a detailed knowledge of their interactions with key enzymes, protein kinase (PK-1 and PK-2) and various phosphodiesterases. NMR studies of the phosphate ring conformation and phosphorus covalency in model enzyme-cyclic nucleotide systems and of cAMP-PK adducts themselves will be pursued. The influence of stereoelectronic effects on chair-twist equilibria of the phosphate ring will be assessed by 1 H NMR. New synthetic investigations of neutral cyclic nucleotide derivatives are aimed at: 1) prodrug delivery of known or potential antivirals and antitumor agents, with a focus on previously targeted thymidylate synthase in thymidine kinase-deficient drug- resistant HSV-1 mutants; and, 2) potential cAMP or cGMP antagonist/agonist molecules for study in Dictyostelium discoideum/cAMP receptor protein systems and with cGMP-activated phosphodiesterases. Biological activities will be determined collaboratively. Certain P (III)-containing cyclic nucleotides will serve as precursors to models with valuable biological properties or useful in dinucleotide synthesis. A thorough knowledge of the conformational properties of the 1,3,1- oxazaphosphorinane ring system of the clinically valuable antitumor agent cyclophosphamide will be pursued as a partial basis for understanding its activity and the design of improved drugs. Specifically, NMR and X-ray crystallographic studies should yield knowledge of the influence of stereoelectronic effects in determining conformation. Detailed knowledge of the scope and mechanism of the formation of azetidines from certain 1,3,2-oxazaphosphorinanes will be sought. The eventual target is biologically active azetidinones. 17 O NMR studies will be aimed at the non-degradative correlation of 17 0 spectral parameters with phosphorus configuration in biologically important P-chiral nucleoside-derived phosphate triesters, phosphonates, and phosphoramidates. A new phosphite to phosphonate photo-Arbuzov rearrangement will be applied to the synthesis of novel antivirals based on acyclic nucleosides and 2',3'-dideoxy- and 2',3'-didehydro-2, 3' -dideoxy ribonucleosides. The focus is on antivirals active against a broad spectrum of viruses including HIV.

在四个不同但相关的领域提出了研究。 一个远距离 目标是更好地理解环核苷酸的作用（在 细胞增殖和不良的特殊和CGMP） 通过详细了解他们与 关键酶，蛋白激酶（PK-1和PK-2）和各种 磷酸二酯酶。 NMR的磷酸环构象和 模型酶循环核苷酸系统中的磷共价和 Camp-PK加合物本身将被追捕。 影响 立体电子对磷酸环的椅子扭转平衡的影响 将通过1 H NMR评估。 中性的新合成研究 环状核苷酸衍生物的目的是：1） 或潜在的抗病毒药和抗肿瘤剂，重点是 胸苷激酶缺乏药物的靶向胸苷合酶 - 抗性HSV-1突变体； 2）潜在的营地或CGMP 用于研究dictyostelium discoideum/CAMP的拮抗剂/激动剂分子 受体蛋白系统和CGMP激活的磷酸二酯酶。 生物活动将由协作确定。 某些p （iii） - 含有循环核苷酸将作为模型的前体 具有有价值的生物学特性或用于二核苷酸合成。 对1,3,1-的构象性质有透彻的了解 临床上有价值的抗肿瘤剂的奥沙唑磷素环系统 环磷酰胺将被作为理解其部分的部分基础 活性和改进药物的设计。 具体而言，NMR和X射线 晶体学研究应得出有关影响的知识 立体电代效应在确定构象中。 详细的知识 从某些的 将寻求1,3,2-氧气磷酸磷酸。 最终的目标是 生物活性氮杂季酮。 17 O NMR研究将针对17 0的非降解相关性 生物学上具有磷构型的光谱参数 重要的p-手续核苷衍生的磷酸三角体，磷酸盐，， 和磷酰胺。 一种新的磷酸盐磷酸磷酸盐照片 - 阿布佐夫重排将是 应用于基于无环核苷的新型抗病毒药的合成 以及2'，3'-二维和2'，3'-二氢-2，3' - 二氧核糖核苷。 重点是针对广泛病毒的抗病毒药 包括艾滋病毒。