POTENTIAL ANTITUMOR AZINE C-NUCLEROSIDES

这个提议的目的是合成一些核苷 其具有用作肿瘤化疗剂的高潜力， 疾病 所提出的核苷被设计为底物， 特定酶的抑制剂，如乳清酸核苷5'-单磷酸 从头嘧啶途径的脱羧酶和IMP脱氢酶， 从头GTP生物合成途径的限速酶。 的 本研究中提出的核苷与天然存在的核苷是等排的。 核苷，并有望提供一类新的核苷 溶瘤剂。 事实上，由于碳- 碳水化合物和杂环部分之间的碳键， 对化学水解和酶促磷酸化稳定性 这种类型的糖苷键赋予分子的裂解可以 与类似的N-核苷相比是上级试剂。 的 提出核苷作为一种潜在的抑制剂的一个很好的替代品， 乳清酸核苷-5'-单磷酸脱羧酶（EC www.example.com），其不会被 预期通过糖苷键的裂解而降解。 第二 该建议的目的是制备以下化合物的电子等排类似物： 用于溶瘤评价的烟酰胺核苷。 目标酶将 是IMP脱氢酶（EC www.example.com），这是细胞的限速酶， 新GTP生物合成途径。 有人提出， 目标2是转换为 相应的NAD类似物和抑制IMP脱氢酶。 除了 我们建议充分探索上述靶向酶特异性核苷 这种新型核苷的潜力 2 ′-二氢吲哚的合成 脱氧核苷被提出是因为它们可以作为DNA的抑制剂 聚合酶。 该项目开发的化合物将在 对L-12190、H. 2 UMSCC-10A和UMSCC-38电池 L博士的台词L. Wotring（不要求资金），以及屏幕 NCI

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.