SYNTHESIS OF ANTITUMOR/VIRAL PYRIMIDINE C-NUCLEOSIDES

根据我们实验室的基本原理和最新发现，我们计划 在图1中合成C-核苷衍生物以研究它们的 最终应用于癌症的生物物理和生化性质- 相关的化疗。 A)5‘-羟基膦酸酯和5’-甲基膦酸衍生物 (β-D-呋喃核糖)-烟酰胺，6-(β-D- 4-(β-D-呋喃核糖)-异烟酰胺和 2-(β-D-呋喃核糖)异烟酰胺。(第1类)。这些类似物 将在体外和体内研究它们的抗癌活性， 与它们抑制脱氢酶的能力有关，特别是对 癌症相关酶，IMP-脱氢酶。 B)烟酰胺核苷部分被取代的NAD类似物 被核糖基吡啶取代，和/或焦磷酸片段被取代 亚甲基双(膦)酸盐。(第2类)。这些类似物将被研究 它们及其对脱氢酶的抑制活性 (尤其是癌症相关的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- 脱氮腺苷(c-ADR)、2‘-脱氧-9-脱氮鸟苷(c-GDR)和2’-脱氧- 9-去氮胞苷(c-IDR)。它们是寡聚-dt、-dc、-da和- 分别为DG(第3类)。这些合成的C-齐聚物 核苷将被研究它们是否与 针对核酸酶的C-核苷酸的互补同源低聚物将是 学习。双螺旋的物理和生化性质 也将进行研究。 D)含有有限数量的C-核苷酸的几个杂低聚物 (第4类)。这些合成的低聚物如果形成，将被研究 双螺旋与天然核苷酸的互补低聚物。 [例如，TT...T-CT-TT...T带有寡聚-A]。这些低聚物的稳定性 对抗核酸酶的作用将被研究。物理和生物化学 还将研究双螺旋的稳定性。 E)几种C-核苷的5‘-二磷酸盐和三磷酸盐的研究 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5类) F)大量有希望的衍生品，供进一步评估 最终应用于临床。

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.