Synthesis, and in vitro enzymatic and antiviral evaluation of d4T polyphosphate derivatives as chain terminators.
A series of d4T di- or triphosphate derivatives have been synthesized and evaluated as effective substrates for HIV-1 RT, and also tested for their in vitro anti-HIV activity. The steady-state kinetic study of compounds 1-4 in an enzymatic incorporation assay by HIV-1 RT follows Michaelis-Menten profile. In addition, compounds 2-4 are able to inhibit HIV-1 replication to the same extent as d4T and d4TMP in MT-4 cells, as well as in CEM/0 cells and CEM/TK(-) cells. The data suggests that these d4T polyphosphate derivatives are hydrolyzed to d4T and rephosphorylated to d4TTP before exerting their antiviral activity.
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Shiqiong
S
Yang
Christophe
C
Pannecouque
Piet
P
Herdewijn
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D054306:Dideoxynucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D011122:Polyphosphates / Q000737:chemistry*; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013938:Thymidine Monophosphate / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
C578869:3'-deoxy-2',3'-didehydrothymidine 5'-diphosphate; C578867:3'-deoxy-2',3'-didehydrothymidine P2-ethyl 5'-P1-diphosphate; D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D011122:Polyphosphates; C578868:bis(3'-deoxy-2',3'-didehydrothymidine) 5',5''-P1,P2-diphosphate; D013938:Thymidine Monophosphate; D018119:Stavudine; D054303:HIV Reverse Transcriptase