CYCLIC NUCLEOTIDE AND CYCLOPHOSPHAMIDE DERIVATIVES

环核苷酸和环磷酰胺衍生物

• 批准号: 3163435
• 负责人: WESLEY G BENTRUDE
• 金额: $ 20.64万
• 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 1989-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3163435
• 关键词: X ray crystallography; antineoplastics; cis trans isomerization; conformation; cyclic AMP; cyclic nucleoside monophosphate; cyclophosphamide; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; free radicals; microsomes; neoplastic transformation; nuclear magnetic resonance spectroscopy; phosphorus; photochemistry; radiotracer

The overall aims and objectives of the proposed research are several: 1) to understand more precisely the molecular aspects of the interaction of the phosphate ring of cyclic 3 feet,5 feet-nucleoside monophosphates with intracellular enzymes with the ultimate target the normalization of processes which control neoplastic transformation; 2) to devise new potential antitumor and antiviral prodrugs based on cyclic 3 feet,5 feet nucleoside monophosphate; neutral cyclic nucleotide derivatives, and certain 3 feet and 5 feet nucleoside monophosphate diesters; 3) to prepare steriospecifically 0-isotope labeled phosphates of biological interest and then correlate 17-O NMR spectral parameters with phosphorus configuration and conformation; 4) to gain a thorough understanding of the conformational features of the 1,3,2-oxazaphosphoriane ring of cyclophosphamide and diastereomeric ring-substituted derivatives and their realationship to ease of microsomal oxidation potentiation and overall therapeutic selectivity; 5) to survey the synthetic and mechanistic aspects of a newly discovered reaction generating N-substituted azetidines with the potential for preparation of biologically interesting Beta-lactams; 6) to utilize newly discovered and postulated new free radical chain reactions of hydridophosphoranes to prepare pentacovalent phosphorous products not otherwise easily available. To these ends new synthetic methods based on cyclic tervalent phosphorus intermediates will be devised for the preparation of neutral derivatives of 3feet,5 feet-cyclic nucleoside monophosphates with a variety of functionality at phosphorus. Collaborative testing in enzyme, cellular and in vivo systems will be carried out, including the assessment of antitumor and antiviral properties. 1H, 13C, and 31p NMR techniques will be to characterize the phosphate ring conformations of the neutral cyclic nucleotide derivatives, assign phosphorus configuration, and relate geometry to biological activity. NMR techniques similarly will be applied to the 1,3,2-oxazaphosphorinane ring system of cyclophosphamide and key ring-substituted derivatives. 17O NMR techniques will be applied in both systems to molecules prepared by stereospecific reaction pathways.

拟议研究的总体目的和目标是：1） 更准确地理解相互作用的分子方面 循环3英尺，5英尺核苷单磷酸盐的磷酸环，带有 具有最终靶标的细胞内酶的归一化 控制肿瘤转化的过程； 2）设计新 潜在的抗肿瘤和抗病毒原药，基于3英尺（5英尺） 核苷单磷酸盐；中性环状核苷酸衍生物和 某些3英尺和5英尺的核苷单磷酸二酮； 3）准备 骨化0-异位标记的生物学兴趣磷酸盐和 然后将17-O NMR光谱参数与磷构型相关联 和构象； 4）对构象有透彻的理解 环磷酰胺和1,3,2-氧气的磷只足环的特征 非对映体环取代的衍生物及其介绍以简化 微粒体氧化增强和整体治疗选择性； 5）调查新发现的合成和机械方面 产生N-取代的氮杂丁的反应，有潜力 制备生物学上有趣的β-内酰胺； 6）使用新的 发现并假定了新的自由基链反应 液化磷烷基制备五抗磷酸产物而不是 否则很容易获得。 这些目的基于新的合成方法 循环电流磷中间体将设计为 制备3fet，5英尺环状核苷的中性衍生物 具有多种功能在磷的单磷酸盐。 酶，细胞和体内系统中的协作测试将是 进行，包括评估抗肿瘤和抗病毒 特性。 1H，13C和31p NMR技术将是表征 中性环状核苷酸衍生物的磷酸环构象，， 分配磷构型，并将几何形状与生物学联系起来 活动。 NMR技术类似地将 环磷酰胺和钥匙的1,3,2-氧气磷磷蛋白环系统 环取代的衍生物。 17o NMR技术将在两者中应用 通过立体反应途径制备的分子系统。