'Fat' Nucleosides and Nucleotides

描述（由申请人提供）：环扩展（脂肪）嘌呤核苷和核苷酸具有化学，生化，生物物理和医学意义。从化学的角度来看，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。从生物化学的角度来看，它们是嘌呤代谢酶的底物或抑制剂以及那些需要能量辅助因子的丰富来源。在生物物理方面，它们是核酸结构、功能和代谢的潜在极好的探针。从医学上讲，它们为抗癌和抗病毒治疗提供了独特的机会。关于后一个方面，一些“脂肪”核苷最近在体外表现出有效的广谱抗病毒和抗癌活性，对宿主细胞系几乎没有毒性。抗病毒活性包括乙型肝炎病毒和丙型肝炎病毒（HBV和HCV）、西尼罗病毒（WNV）、eb病毒（EBV）、带状疱疹病毒（VZV）、日本脑炎病毒（JEV）、犀牛病毒（RV）、单纯疱疹病毒（HSV-1和HSV-2）和麻疹病毒（MV）。体外抗肿瘤活性包括白血病、肺癌、结肠癌、中枢神经系统癌、黑色素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌。然而，鉴于目前美国对该病毒的健康恐慌，该提案特别关注西尼罗河病毒（WNV）。该建议涉及利用几种“脂肪”核苷进行病毒复制的机制研究，这些核苷在体外表现出强大的抗西尼罗河病毒活性。将探索两种被认为最可行的特定病毒抑制模式。根据提出的机制研究的结果，已经制定了适当的合成策略，以进一步对“脂肪”核苷和核苷酸进行结构修饰，从而最终发现最有效的抗西尼罗河病毒抗病毒药物，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.