Carbocyclic Nucleoside Isosteres as Potential Antitumor and Antiviral Agents

双环[3.1.0]己烷模板作为聚合反应平台的研究 新型构象锁定的碳环核苷的构建继续产生许多 有趣的化合物我们使用这些修饰的核苷的目的是：（1）确定 参与核苷生物化学的酶的构象偏好， 核苷酸和寡核苷酸;以及（2）开发尽可能多的选定化合物 抗肿瘤/抗病毒药物基于我们对其生化作用机制的理解。 这些努力导致发现了N-甲氨基碳酰胸苷（N-MCT），一种化合物 有效对抗疱疹病毒1和2，以及与Kaposi相关的人类疱疹病毒8 肉瘤。今年，我们通过合同完成了N-MCT（65 g）的半制备合成。的 许可公司N-Scientific收到了部分材料，并与NIAID科学家一起， 研究了口服药物对HSV-2感染小鼠的活性。成功 结果促使该公司开始在HSV-2豚鼠阴道模型中进行正在进行的研究。 未来的毒理学和药理学研究将继续进行。动物毒性研究， D-carba-T（碳环胸苷），一种成功激酶化的核苷， 在HIV感染细胞中的动力学延迟链终止剂已经被批准。小说 该试剂的作用机理最近发表在J. Med. Chem. 携带新核苷的寡核苷酸，所述新核苷被锁定在一个特定的环起皱上 是一个越来越受关注的领域。北鸟嘌呤和南鸟嘌呤的替换建立在一个 双环[3.1.0]己烷模板在凝血酶的几个位点首次揭示了 糖构象和核碱基的配置对糖构象的单独贡献。 适体的稳定性。这些结果最近发表在《核酸研究》上。 南北双环[3.1.0]己烯的联合合成及抗HIV活性研究 在此期间，核武器被发现。研究结果发表在《化学医学化学》杂志上 这篇论文被选作杂志的封面内页。

The investigation of the bicyclo[3.1.0]hexane template as a platform for the construction of novel conformationally locked carbocyclic nucleosides continues to yield many interesting compounds. We use these modified nucleosides with the intent of: (1) determining the conformational preferences of enzymes involved in the biochemistry of nucleosides, nucleotides, and oligonucleotides; and (2) developing selected compounds as possible antitumor/antiviral drugs based on our understanding of their biochemical mechanism of action. These efforts have resulted in the discovery of N-methanocarbathymidine (N-MCT), a compound active against herpes viruses 1 and 2, as well as human herpesvirus 8 associated with Kaposi sarcoma. This year, we completed a semi-prep synthesis of N-MCT (65 g) via contract. The licensing company, N-Scientific, received part of this material and with NIAID scientists they have studied the oral activity of the drug against HSV-2 in infected mice. The successful results prompted the company to initiate ongoing studies in a HSV-2 guinea pig vaginal model. Future toxicological and pharmacological studies will follow. Animal toxicity studies with D-carba-T (carbocyclic thymidine), a successfully kinased nucleoside that functions as a kinetic delayed chain terminator in HIV-infected cells, have been approved. The novel mechanism of action of this agent was recently published in J. Med. Chem. The synthesis of oligonucleotides carrying novel nucleosides that are locked toward one specific ring puckering is a field of increasing interest. The substitution of North and South guanines built on a bicyclo[3.1.0]hexane templateat several sites of the thrombin revealed for the first time the separate contributions of the sugar conformation and the disposition of the nucleobase to the stability of the aptamer. These results have appeared recently in the Nucleic Acids Research. The combined syntheses and anti-HIV studies on North and South bicyclo[3.1.0]hexene nucleosides was achieved during this period. The results appeared in the journal ChemMedChem and the paper was selected for display in the inside cover of the journal.