Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach.
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.
Petersen
Lene
L
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Jørgensen
Per T
PT
Nielsen
Claus
C
Hansen
Thomas H
TH
Nielsen
John
J
Pedersen
Erik B
EB
D002460:Cell Line; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009154:Mutation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018119:Stavudine / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry*
C498573:2,2-dimethylthiopropionic acid S-(2-((4-(4-benzyl-3-ethoxymethyl-5-isopropyl-2,6-dioxo-3,6-dihydro-2H-pyrimidine-1-carbonyl)phenoxy)-(5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,5-dihydrofuran-2-ylmethoxy)phosphoryloxy)ethyl) ester; C498575:2,2-dimethylthiopropionic acid S-(2-((4-(6-(3,5-dimethylbenzyl)-5-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethoxymethyl)phenoxy)-(5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,5-dihydrofuran-2-ylmethoxy)phosphoryloxy)ethyl) ester; C498574:NNRTI MKC-442; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides; D013938:Thymidine Monophosphate; D014498:Uracil; D018119:Stavudine; C083858:emivirine