'Fat' Nucleosides and Nucleotides

描述（由申请人提供）：扩环（脂肪）嘌呤核苷和核苷酸具有化学、生物化学、生物物理和医学意义。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是有趣的。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的丰富来源，以及需要能量辅因子的那些。在生物物理学方面，它们是核酸结构、功能和代谢的潜在优秀探针。在医学上，它们为抗癌和抗病毒治疗提供了独特的机会。关于后一个方面，许多“脂肪”核苷最近在体外表现出有效的、广谱的抗病毒和抗癌活性，对宿主细胞系几乎没有毒性（如果有的话）。抗病毒活性包括B和C型肝炎病毒（HBV和HCV）、西尼罗河病毒（WNV）、EB病毒（EBV）、带状疱疹病毒（VZV）、日本脑炎病毒（JEV）、鼻病毒（RV）、单纯疱疹（HSV-1和HSV-2）病毒和麻疹病毒（MV）。体外抗癌活性包括白血病、肺癌、结肠癌、CNS、黑素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌。然而，该提案特别关注西尼罗河病毒（WNV），因为该病毒目前在美国引起健康恐慌。该提案涉及采用几个“脂肪”核苷的病毒复制的机制研究，这些核苷在体外表现出有效的抗西尼罗河病毒活性。将探索被认为最可行的两种特定病毒抑制模式。适当的合成策略已经到位，以进一步结构修饰的“脂肪”核苷和核苷酸，根据所提出的机制研究的结果，以便最终发现最有效的抗病毒药物对西尼罗河病毒与令人沮丧的，如果有的话，人类毒性。

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.