CYCLIC NUCLEOTIDES, CYCLOPHOSPHAMIDES, BIOPHOSPHONATES

环状核苷酸、环磷酰胺、二磷酸盐

基本信息

批准号：
2192659
负责人：
WESLEY G BENTRUDE
金额：
$ 24.92万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1975
资助国家：
美国
起止时间：
1975-06-01 至 1999-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2192659
关键词：
2'3' dideoxynucleoside Dictyostelium X ray crystallography acyclovir antiAIDS agent 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 nitrogenous heterocyclic compound nuclear magnetic resonance spectroscopy phosphamide phosphates phosphites phosphodiesterases phosphonate phosphorus prodrugs protein kinase radiotracer thymidylate synthase

2'3' dideoxynucleoside Dictyostelium X ray crystallography acyclovir antiAIDS agent 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 nitrogenous heterocyclic compound nuclear magnetic resonance spectroscopy phosphamide phosphates phosphites phosphodiesterases phosphonate phosphorus prodrugs protein kinase radiotracer thymidylate synthase

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项目摘要

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。