POTENTIAL ANTITUMOR AZINE C-NUCLEROSIDES

这项提议的目标是合成一些核苷 它们具有作为肿瘤化疗药物的高潜力 疾病。建议的核苷被设计为底物和 特定酶的抑制剂，如5‘-一磷酸核苷 从头开始的嘧啶途径脱羧酶和IMP脱氢酶 GTP生物合成途径的限速酶。这个 这项研究中提出的核苷是等空间的，是自然存在的 并有望提供一类新的核苷 溶瘤剂。事实上，提议的核苷，由于碳- 碳水化合物和杂环部分之间的碳键，以及 对化学水解物和酶促磷酸水解物的稳定性 这种类型的糖苷结合给予分子的切割可以 与类似的N-核苷相比是更好的试剂。这个 建议的核苷作为一种潜在的抑制剂的良好替代品 奥替替丁-5‘-单磷酸脱羧酶(EC 4.1.1.23)，不会 预计会通过糖苷键的裂解而降解。第二 本提案的目的是制备异构体类似物 用于溶瘤评价的烟酰胺核苷。靶标酶将 BE IMP脱氢酶(EC 1.1.1.205)，脱氢酶的限速酶 Novo GTP生物合成途径。有人提出，黄连的核苷 目标2是优秀的候选人，可以转化为 相应的NAD类似物并抑制IMP脱氢酶。除了……之外 以上靶向的酶特异性核苷我们建议充分发掘 这类新核苷的潜力。2‘-二氢呋喃的合成 脱氧核苷被提出，因为它们可以作为dna的抑制剂。 聚合酶。在该项目中开发的化合物将在#年进行评估 抗L-12190、H.Ep.2个UMSCC-10A和UMSCC-38细胞 L.L.Wotring博士的台词(不要求资金)，以及 美国国家情报局。

The objective of this proposal is to synthesize a number of nucleosides which have a high potential for use as chemotherapeutics in neoplastic diseases. The proposed nucleosides are designed to be substrates and inhibitors of specific enzymes, such as, orotidine 5'-monophosphate decarboxylase of the de novo pyrimidine pathway and IMP dehydrogenase, the rate limiting enzyme of the de novo GTP biosynthetic pathway. The nucleosides proposed in this study are isosteric with naturally occurring nucleosides and are expected to provide a new class of nucleoside oncolytic agents. Indeed, the proposed nucleosides, due to the carbon- carbon linkage between the carbohydrate and heterocyclic moieties, and the stability toward both chemical hydrolytic and enzymatic phosphorylytic cleavage that this type of glycosidic bound imparts of the molecule, may be superior agents in comparison to the analogous N-nucleosides. The proposed nucleosides an excellent alternative as a potential inhibitor of orotidine-5'-monophosphate decarboxylase (EC 4.1.1.23) which would not be expected to be degraded by cleavage of the glycosidic bond. The second objective of this proposal is to prepare isosteric analogues of nicotinamide nucleoside for oncolytic evaluation. The target enzyme would be IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of the de novo GTP biosynthetic pathway. It is proposed that the nucleosides of objective 2 are excellent candidates to be converted into the corresponding NAD analogues and inhibit IMP dehydrogenase. In addition to the above targeted enzyme-specific nucleosides we propose to fully explore the potential of this new class of nucleosides. The synthesis of 2'- deoxynucleosides are proposed since they may act as inhibitors of DNA polymerase. The compounds developed on this project would be evaluated in an in vitro screen against L-12190, H.Ep. 2 UMSCC-10A and UMSCC-38 cell lines by Dr. L. L. Wotring (no funds requested), as well as the screen of N.C.I.