SYNTHESIS OF ANTITUMOR/VIRAL PYRIMIDINE C-NUCLEOSIDES

根据基本原理和我们实验室的最新研究结果，我们计划 合成图1中的C-核苷衍生物，以研究其 生物物理和生物化学性质，用于癌症的最终应用- 相关化疗 a）5-羟基膦酸酯和5-甲基膦酸酯衍生物， （β-D-呋喃核糖基）-烟酰胺，6-（β-D- 4-（β-D-呋喃核糖基）-异烟酰胺和 2-（β-D-呋喃核糖基）异烟酰胺。 （第1类）。 这些类似物 将在体外和体内研究其抗癌活性， 与其抑制脱氢酶的能力有关，特别是对于 癌症相关酶IMP-脱氢酶。 B）其中烟酰胺核苷部分被置换的NAD类似物 被核糖基吡啶取代，和/或焦磷酸片段被 亚甲基双（膦酸酯）。 （第2类）。 这些类似物将被研究 及其抗真菌酶的抑制活性 （尤其是癌症相关IMP-脱氢酶）、NAD-水解酶和 聚ADP-核糖聚合酶。 c）2 '-脱氧-假-异胞苷（c-CdR）、2'-脱氧-9-脱氧-异胞苷（c-CdR）、2 '-脱氧-异胞苷（c-CdR）、2'-脱氧-异胞苷（c-CdR）和2 '-脱氧-异胞苷（c-CdR）的同源寡聚物。 去氮腺苷（c-AdR）、2 ′-脱氧-9-去氮鸟苷（c-GdR）和2 ′-脱氧- 9-去氮肌苷（c-IdR）。 它们是寡聚-dT、-dC、-dA和- dG（3类）。 这些合成的C- 将研究核苷是否形成双螺旋， 针对核酸酶的C-核苷酸的互补同源寡聚体将是 研究了 双螺旋的物理和生化特性 也将被研究。 d）含有有限量的C-核苷酸的几种异源寡聚体 （第4类）。 这些合成低聚物将被研究，如果他们形成 双螺旋与天然核苷酸的互补寡聚体。 [e.g., TT... T-cT-TT... T与寡聚-A]。 这些低聚物的稳定性 对核酸酶进行研究。 物理和生物化学 还将研究双螺旋的稳定性。 e）要研究的几种C-核苷的5 '-二-和三-磷酸 各种聚合酶的底物特异性（例如，DNA-和 RNA聚合酶、逆转录酶和多核苷酸 磷酸化酶）。 （第五类） f）大量有前途的衍生物，用于进一步评估， 最终临床应用。

On the basis of rationale and recent findings in our Laboratory, we plan to synthesize C-nucleoside derivatives in Figure 1 to study their biophysical and biochemical nature for eventual applications of cancer- related chemotherapy. a) 5'-Hyrogenphosphonate and 5'-methylphosphonate derivatives of 5- (beta-D-ribofuranosyl)-nicotinamide, 6-(beta-D- ribofuranosyl)picolinamide, 4-(beta-D-ribofuranosyl)-isonicotinamide and 2-(beta-D-ribofuranosyl)isonicotinamide. (Class 1). These analogues will be studied for their anticancer activity in vitro and in vivo, in relation to their capacity to inhibit dehydrogenases, especially for the cancer related enzyme, IMP-dehydrogenase. b) NAD analogues in which the nicotinamide riboside moiety is displaced by a ribosylpyridine, and/or the pyrophosphate fragment is displaced by methylene bis(phosphonate). (Class 2). These analogues will be studied for their and their inhibitory activity against dehydrogenases (especially cancer related IMP-dehydrogenase), NAD-hydrolases and poly(ADP-ribose) polymerase. c) Homo-oligomers of 2'-deoxy-pseudo-isocytidine (c-CdR), 2'-deoxy-9- deazaadenosine (c-AdR), 2'-deoxy-9-deazaguanosine (c-GdR) and 2'-deoxy- 9-deazainosine (c-IdR). They are analogues of oligo-dT, -dC, -dA and - dG respectively (Class 3). These synthetic homo-oligomers of C- nucleosides will be studied as to whether they form a double helix with complementary homo-oligomers of C-nucleotides against nucleases will be studied. The physical and biochemical properties of the double helix will also be studied. d) Several hetero-oligomers containing a limited amount of C-nucleotides (Class 4). These synthetic oligomers will be studied if they form double helix with complementary oligomers of natural nucleotides. [e.g., TT...T-cT-TT...T with oligo-A]. The stability of these oligomers against nucleases will be studied. The physical and biochemical stabilities of the double helix will also be studied. e) Several 5'-di- and tri-phosphates of C-nucleosides to study for substrate specificity of various polymerizing enzymes (e.g., DNA- and RNA-polymerases, reverse transcriptases and polynucleotide phosphorylases). (Class 5) f) Large amounts of promising derivatives for further evaluation for eventual clinical application.