Cytidine deaminase inhibitors

以含七元二氮平酮苷元的双环[3.1.0]己烷核苷为原料合成胞苷脱氨酶抑制剂。为了研究有效抑制CDA的糖部分的构象要求，我们在稳定的双环[3.1.0]己烷支架上构建了1,3-二氮平-2- 1糖基，锁定在伪旋转循环的极北和极南构象。这些衍生物与一种基于简单环戊烷假糖的柔性抑制剂一起，对其抑制脱胺反应的能力进行了评估。基于结合二氮平酮核糖体的人类CDA晶体结构，我们得出结论，锁定在南半球的碳环抑制剂应该比其北对跖点更好地抑制CDA。生物学研究支持这一结论，但表明柔性类似物的效力是首选的南方锁定衍生物的100倍（核酸研讨会系列第52期，2008年，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).