Fused Pyrimidine (IsoA) Nucleosides:Design and Synthesis

描述（由申请人提供）：尽管在寻找有希望的线索， 新的化疗药物，目前使用的耐药性的出现， 治疗，以及缺乏一个单一的候选人被确定， 保留作为治疗癌症的方法，明确指出需要继续 生物学调查。众所周知，核苷是 许多生物系统的基本组成部分，因此， 修饰的核苷为大量的研究提供了动力 由于它们与天然存在的 核苷存在着错综复杂的关系， 嘌呤和嘧啶核苷酸代谢、细胞增殖和肿瘤细胞 分化由于这种关系， 核苷酸代谢和DNA合成可用作化疗剂 治疗癌症的方法。在这方面，DNA的生物作用 甲基化涉及DNA结合蛋白的抑制或增强。 DNA通过形成特定的甲基化模式来编码信息， 基因表达是通过在DNA-蛋白质过程中“阅读”这些模式来确定的。 在相互作用中，DNA甲基化的破坏成为一个有吸引力的目标， 疗法DNA甲基化的破坏可以通过几种方式完成， 特别是通过抑制DNA甲基转移酶（DNA MeTase）和/或 S-腺苷高半胱氨酸水解酶（SAHase），两者都建立了细胞靶点 用于抗病毒、抗寄生虫和抗癌剂。修饰的核苷， 特别是碳环核苷。已经表现出显著的抑制作用， 抗SAHase和DNA MeTase的活性。我们在此提出了合成和 一系列新的碳环核苷的生物学研究， 具有关键的结构特征，这将赋予它们强大的抑制作用 针对上述酶的特性。我们相信这种抑制 导致有意义的生物活性，以及诱导细胞 分化

DESCRIPTION (provided by applicant): Despite promising leads in the search for new chemotherapeutic agents, the emergence of resistance to presently used treatments, as well as the lack of a single candidate to be identified and retained as a cure for cancer, clearly points to the need for continued biological investigations. It is well recognized that nucleosides are the fundamental building blocks of many biological systems and as a result, modified nucleosides have provided the impetus for a plethora of investigations due to their inherent structural resemblance to the naturally occurring nucleosides. There exists an intricately intertwined relationship between purine and pyrimidine nucleotide metabolism, cell proliferation and tumor cell differentiation. Because of this relationship, inhibition of key enzymes in nucleotide metabolism and DNA synthesis can be used as a chemotherapeutic approach to treating cancer. In this regard, the biological role of DNA methylation involves either inhibition or enhancement of DNA binding proteins. DNA encodes information by forming specific patterns of methylation, and since gene expression is determined by "reading" these patterns during DNA-protein interactions, disruption of DNA methylation becomes an attractive target for therapy. Disruption of DNA methylation can be accomplished in several ways, in particular, by inhibition of DNA methyltransferase (DNA MeTase) and/or S-adenosylhomocysteine hydrolase (SAHase), both established cellular targets for antiviral, antiparasitic and anticancer agents. Modified nucleosides, in particular the carbocyclic nucleosides. have exhibited significant inhibitory activity against SAHase and DNA MeTase. We propose herein the synthesis and biological investigation of a novel series of carbocyclic nucleosides that possess key structural features that will endow them with potent inhibitory properties against the aforementioned enzymes. We believe this inhibition will result in meaningful biological activity, as well as to induce cell differentiation.