CYCLOPENTENYL NUCLEOSIDE ISOSTERES AS POTENTIAL ANTITUMOR AND ANTIVIRAL AGENTS

构象锁定核苷的同手性合成， 从手性碳环前体发展而来。 双环[3.1.0]己烷 模板法合成构象刚性核苷类似物 在北方，当环丙烷环融合在 环戊烷环的4'和6'碳，而锁定的Southern 当环丙烷的稠合时， 发生在碳1'和6'之间。 AZT类似物在两个锁定 构象未能具有可检测的抗HIV活性。 但 胸苷和腺苷类似物被赋予了有效的和选择性的 对疱疹家族，包括人类的抗病毒活性 巨细胞病毒 当掺入到设计的寡脱氧核苷酸中时， 作为反义试剂，具有以下结构的构象锁定核苷： 北方构象促进了异源双链体的形成 互补RNA显著增加了 温度（Tm）。 这两种类型的构象结合 将核苷锁定到相同的寡脱氧核苷酸中， 产生短的寡聚体，其弯曲类似于 转录和整合因子。 这些预期的抑制作用 特异性转录和整合因子的使用， 弯曲的寡脱氧核苷酸将被利用作为一种可能的 癌症和艾滋病的化疗方法。

Homochiral syntheses of conformationally locked nucleosides were developed from chiral carbocyclic precursors. The bicyclo[3.1.0]hexane template allowed syntheses of conformationally rigid nucleoside analogues in the Northern hemisphere when the cyclopropane ring was fused between carbons 4' and 6' of the cyclopentane ring, while a locked Southern hemisphere conformation was realized when the fusion of the cyclopropane occurred between carbons 1' and 6'. AZT analogues in both locked conformations failed to have detectable anti-HIV activity. However, the thymidine and adenosine analogues were endowed with potent and selective antiviral activity against the herpes family, including human cytomegalovirus. When incorporated into oligodeoxynucleotides designed as antisense agents, the conformationally locked nucleosides with Northern conformations facilitated the formation of the heteroduplexes with the complementary RNA producing significant increases in the melting temperatures (Tm). The incorporation of both types of conformationally locked nucleosides into the same oligodeoxynucleotides is anticipated to produce short oligomers with a bend similar to that induced on DNA by transcription and integration factors. The expected inhibition of these specific transcription and integration factors resulting from the use of bent oligodeoxynucleotides will be exploited as a possible chemotherapeutic approach to cancer and AIDS.