Cytidine deaminase inhibitors

含七元二氮杂环庚酮的双环[3.1.0]己烷核苷的合成 糖苷配基被提议用于开发新型胞苷脱氨酶抑制剂。探讨 为了有效抑制CDA的糖部分的构象要求，我们建立了 稳定双环[3.1.0]己烷支架上的1，3-二氮杂卓-2-酮糖苷配基被锁定在极端 伪旋转旋回的南北构象。与灵活的 抑制剂建立在一个简单的环戊烷pseudogar，这些衍生物进行了评价，其 抑制脱氨基反应的能力。基于人CDA的晶体结构， 结合的二氮杂卓核苷，我们得出结论，碳环抑制剂锁定在 南半球对CDA的抑制作用比其北方对极好。的 生物学研究支持这一结论，但表明柔性类似物 100-比优选的Southern锁定衍生物有效10倍（Nucleic Acids Symposium SeriesNo.52，2008，659-660）。

Syntheses of bicyclo[3.1.0]hexane nucleosides bearing a seven-member diazepinone aglycon were proposed to develop novel inhibitors of cytidine deaminase. To investigate the conformational requirements of the sugar moiety for potent inhibition of CDA, we built the 1,3-diazepin-2-one aglycon on stable bicyclo[3.1.0]hexane scaffolds locked in the extreme North and South conformations of the pseudo-rotational cycle. Together with a flexible inhibitor built on a simple cyclopentane pseudogar, these derivatives were evaluated for their ability to inhibit the deamination reaction. Based on the crystal structure of human CDA with the bound diazepinone riboside, we concluded, that the carbocyclic inhibitor locked in the southern hemisphere should be a better inhibitor for CDA, than its northern antipode. The biological studies supported such conclusion but indicated that the flexible analogue was 100-fold more potent than the preferred southern locked derivative (Nucleic Acids Symposium Series No. 52, 2008, 659-660).