Phosphoramidate ProTides of the Anticancer Agent FUDR Successfully Deliver the Preformed Bioactive Monophosphate in Cells and Confer Advantage over the Parent Nucleoside

被引：101

作者：

McGuigan, Christopher ^{[1
]}

Murziani, Paola ^{[1
]}

Slusarczyk, Magdalena ^{[1
]}

Gonczy, Blanka ^{[1
]}

Vande Voorde, Johan ^{[2
]}

Liekens, Sandra ^{[2
]}

Balzarini, Jan ^{[2
]}

机构：

[1] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales

[2] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 20期

关键词：

FLUORINATED PYRIMIDINES; PRODRUGS; ACTIVATION; PURINE; ANTIMETABOLITES; 5-FLUOROURACIL; DERIVATIVES; NB1011; DESIGN; BVDU;

D O I：

10.1021/jm200815w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid. regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression.

引用

页码：7247 / 7258

页数：12

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