Tomasz J, Vaghefi M M, Ratsep P C, Willis R C, Robins R K
Department of Chemistry, Brigham Young University, Provo, UT 84602.
Nucleic Acids Res. 1988 Sep 12;16(17):8645-64. doi: 10.1093/nar/16.17.8645.
The synthesis of imidodiphosphate analogues of natural nucleoside 5'-diphosphates including adenosine 5'-imidodiphosphate (4a), guanosine 5'-imidodiphosphate (4b), 2'-deoxyadenosine 5'-imidodiphosphate (4c), and 2'-deoxy-guanosine 5'-imidodiphosphate (4d) has been accomplished for the first time. These compounds are the products of the reaction between nucleosides and trichloro [(dichlorophosphoryl)imido] phosphorane in trimethyl phosphate. Some of the major by-products of the reaction including 5'-deoxy-5'-chloro nucleosides are discussed. Compounds 4b, 4c, and 4d are potent inhibitors of ecto-5'-nucleotidase whereas compound 4a also active but less potent inhibitor. Compound 4b is the most potent inhibitor of phosphoribosyl pyrophosphate (PPRP) synthetase which follows by 4c, 4d and 4a. All of these compounds were more potent inhibitor of PPRP-synthetase than ADP or GDP. Ribavirin imidodiphosphate (4e) was also synthesized and tested for its inhibitory effect on ecto-5'-nucleotidase, PPRP-synthetase as well as IMP dehydrogenase. Compound 4e is the most potent inhibitor of IMP dehyrogenase but was a weak inhibitor of the other two enzymes. compound 4a, 4b, 4c and 4d are weak inhibitors of IMP dehydrogenase.
首次完成了包括腺苷5'-亚氨二磷酸（4a）、鸟苷5'-亚氨二磷酸（4b）、2'-脱氧腺苷5'-亚氨二磷酸（4c）和2'-脱氧鸟苷5'-亚氨二磷酸（4d）在内的天然核苷5'-二磷酸的亚氨二磷酸类似物的合成。这些化合物是核苷与三氯[（二氯磷酰基）亚氨基]磷烷在磷酸三甲酯中反应的产物。讨论了该反应的一些主要副产物，包括5'-脱氧-5'-氯核苷。化合物4b、4c和4d是ecto-5'-核苷酸酶的有效抑制剂，而化合物4a也是活性但效力较低的抑制剂。化合物4b是磷酸核糖焦磷酸（PPRP）合成酶最有效的抑制剂，其次是4c、4d和4a。所有这些化合物都是比ADP或GDP更有效的PPRP合成酶抑制剂。利巴韦林亚氨二磷酸（4e）也被合成并测试了其对ecto-5'-核苷酸酶、PPRP合成酶以及IMP脱氢酶的抑制作用。化合物4e是IMP脱氢酶最有效的抑制剂，但对其他两种酶是弱抑制剂。化合物4a、4b、4c和4d是IMP脱氢酶的弱抑制剂。
