'Fat' Nucleosides and Nucleotides

说明(申请人提供)：扩环(脂肪)嘌呤核苷和核苷酸具有化学、生物化学、生物物理和医药价值。从化学的观点来看，它们的合成、结构、稳定性、酸碱性质、芳香性和互变异构平衡都很有趣。从生化角度来看，它们是嘌呤代谢酶的底物或抑制剂的丰富来源，以及那些需要能量辅因子的底物或抑制剂。在生物物理学方面，它们可能是研究核酸结构、功能和新陈代谢的极佳探针。在医学上，它们为抗癌和抗病毒治疗提供了独特的机会来源。在后一方面，一些“脂肪”核苷最近在体外表现出了强大的、广谱的抗病毒和抗癌活性，对宿主细胞株几乎没有毒性。抗病毒活性包括乙型和丙型肝炎病毒、西尼罗河病毒、EB病毒、Vericella带状疱疹病毒、日本脑炎病毒、犀牛病毒、单纯疱疹病毒、麻疹病毒。体外抗癌活性包括白血病、肺癌、结肠癌、中枢神经系统、黑色素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌。然而，鉴于西尼罗河病毒(WNV)在美国目前的健康恐慌，这项建议特别关注这种病毒。该提案涉及使用几个在体外表现出强大的抗西尼罗病毒活性的“脂肪”核苷对病毒复制进行的机制研究。将探索两种被认为最可行的病毒抑制特定模式。已经制定了适当的合成策略，根据拟议的机械性调查的结果，对“脂肪”核苷和核苷酸进行进一步的结构改造，以最终发现对西尼罗河病毒最有效的抗病毒药物，如果有的话，对人体的毒性很低。

DESCRIPTION (provided by applicant): Ring-expanded (Fat) purine nucleosides and nucleotides are of chemical, biochemical, biophysical and medicinal interest. From a chemical standpoint, their synthesis, structure, stability, acid-base properties, aromaticity, and tautomeric equilibria are interesting. From a biochemical perspective, they are an abundant source of substrates or inhibitors of enzymes of purine metabolism, as well as of those requiring energy cofactors. In biophysical terms, they are potentially excellent probes for nucleic acid structure, function, and metabolism. Medicinally, they offer a unique source of opportunities for anticancer and antiviral therapy. With regard to this latter aspect, a number of "fat" nucleosides have recently exhibited potent, broad-spectrum antiviral and anticancer activities in vitro with little toxicity, if any, to the host cell lines. The antiviral activities include hepatitis B and C virus (HBV and HCV), West Nile virus (WNV), Epstein-Barr virus (EBV), Vericella Zoster virus (VZV), Japanese Encephalitis virus (JEV), Rhino virus (RV), Herpes Simplex (HSV-1 and HSV-2) viruses, and Measles virus (MV). The in vitro anticancer activities include leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. However, this proposal specifically focuses on the West Nile Virus (WNV) in light of the current health scare of this virus in US. The proposal concerns mechanistic investigations of viral replication employing a few "fat" nucleosides that have exhibited potent in vitro anti-WNV activity. Two specific modes viral inhibition, which are deemed most viable, will be explored. Appropriate synthetic strategies have been put in place for further structural modifications of "fat" nucleosides and nucleotides, contingent upon the outcome of the proposed mechanistic investigations, so as to eventually discover most potent antivirals against WNV with dismal, if any, human toxicity.