作为胞苷脱氨酶抑制剂的构象锁定碳环1,3-二氮杂环庚烷酮核苷的合成。

Synthesis of conformationally locked carbocyclic 1,3-diazepinone nucleosides as inhibitors of cytidine deaminase.

作者信息

Ludek Olaf R, Schroeder Gottfried K, Wolfenden Richard, Marquez Victor E

机构信息

Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.

出版信息

Nucleic Acids Symp Ser (Oxf). 2008(52):659-60. doi: 10.1093/nass/nrn333.

DOI:10.1093/nass/nrn333

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2730941/

Abstract

We synthesized a series of carbocyclic nucleoside inhibitors of cytidine deaminase (CDA) based on a seven-membered 1,3-diazepin-2-one moiety. In the key step, the seven-membered ring was formed by a ring-closing-metathesis reaction. Therefore, the bis-allyl-urea moiety had to be protected by benzoylation in order to obtain an orientation suitable for ring closure. To our surprise, the analogue built on a flexible sugar template (4) showed a 100-fold stronger inhibition of CDA than the derivative with the preferred south-conformation.

摘要

我们基于七元1,3-二氮杂环庚-2-酮部分合成了一系列胞苷脱氨酶（CDA）的碳环核苷抑制剂。在关键步骤中，通过关环复分解反应形成七元环。因此，双烯丙基脲部分必须通过苯甲酰化进行保护，以获得适合环化的取向。令我们惊讶的是，基于柔性糖模板构建的类似物（4）对CDA的抑制作用比具有优选南构象的衍生物强100倍。

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本文引用的文献

1

Structure of human cytidine deaminase bound to a potent inhibitor.

J Med Chem. 2005 Feb 10;48(3):658-60. doi: 10.1021/jm0496279.

2

Synthesis of 1,3-diazepin-2-one nucleosides as transition-state inhibitors of cytidine deaminase.

J Med Chem. 1980 Jul;23(7):713-5. doi: 10.1021/jm00181a001.

3

Cyclic urea nucleosides. Cytidine deaminase activity as a function of aglycon ring size.

J Med Chem. 1981 Jun;24(6):662-6. doi: 10.1021/jm00138a003.

4

Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations.

Science. 1991 May 31;252(5010):1278-84. doi: 10.1126/science.1925539.

5

Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2'-deoxycytidine by human cytidine deaminase.

Cancer Chemother Pharmacol. 1992;30(1):7-11. doi: 10.1007/BF00686478.

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