Petersen Lene, Jørgensen Per T, Nielsen Claus, Hansen Thomas H, Nielsen John, Pedersen Erik B
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
J Med Chem. 2005 Feb 24;48(4):1211-20. doi: 10.1021/jm040845b.
This paper reports the synthesis and the antiviral activities of new double-prodrugs against HIV based on the known mixed SATE (S-acyl-2-thioethyl) prodrug approach. The monophosphate of the nucleoside reverse transcriptase inhibitor (NRTI) d4T was masked with one SATE group and one aromatic group through which a nonnucleoside reverse transcriptase inhibitor (NNRTI) was linked. Double-prodrug 1 was a hybrid between d4T monophosphate and the known NNRTI MKC-442, which were linked through a labile p-hydroxybenzoyl protection group in the N-3 position of MKC-442. Double-prodrugs 2 and 3 were conjugates between d4T monophosphate and the new NNRTIs 15 and 19 linked through a stable phenolic linker that was a part of the N-1 substituents of the NNRTIs. The double-prodrugs 1, 2, and 3 all had good activities against wild-type HIV-1, Y181C mutant, and also against a HIV-2 strain that was resistant to NNRTIs.
本文报道了基于已知的混合SATE（S-酰基-2-硫代乙基）前药方法合成的新型抗HIV双前药及其抗病毒活性。核苷逆转录酶抑制剂（NRTI）司他夫定单磷酸酯通过一个SATE基团和一个芳香基团进行掩蔽，通过该芳香基团连接了一种非核苷逆转录酶抑制剂（NNRTI）。双前药1是司他夫定单磷酸酯与已知的NNRTI MKC-442之间的杂合物，它们通过MKC-442 N-3位的不稳定对羟基苯甲酰保护基团相连。双前药2和3是司他夫定单磷酸酯与新型NNRTIs 15和19之间的缀合物，通过一个稳定的酚类连接基团相连，该连接基团是NNRTIs N-1取代基的一部分。双前药1、2和3对野生型HIV-1、Y181C突变体以及对NNRTIs耐药的HIV-2毒株均具有良好的活性。
