Novel Antiviral C5-Substituted Pyrimidine Acyclic Nucleoside Phosphonates Selected as Human Thymidylate Kinase Substrates

作者：Topalis Dimitri; Pradere Ugo; Roy Vincent; Caillat Christophe; Azzouzi Ahmed; Broggi Julie; Snoeck Robert; Andrei Graciela; Lin Jay; Eriksson Staffan; Alexandre Julie A C; El Amri Chahrazade; Deville Bonne Dominique; Meyer Philippe; Balzarini Jan; Agrofoglio Luigi A^*

来源：Journal of Medicinal Chemistry, 2011, 54(1): 222-232.

DOI：10.1021/jm1011462

Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine monophosphate (TMP) kinase, but not for uridine monophosphate cytosine monophosphate (UMP-CMP) kinase, which is in contrast to cidofovii Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC50 = 3 mu M) and against varicella zoster virus in vitro (IC50 = 0 19 mu M), in contrast to the corresponding inactive (Z) derivatives Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates

• 出版日期2011-1-13
• 单位河北医科大学