141171-21-3Relevant articles and documents
New Thymidine Triphosphate Analogue Inhibitors of Human Immunodeficiency Virus-1 Reverse Transcriptase
Ma, Qi-Feng,Bathurst, Ian C.,Barr, Philip J.,Kenyon, George L.
, p. 1938 - 1941 (1992)
Several novel imidotriphosphate analogues of thymidine have been synthesized and have been shown to be effective inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT).When the α,β-bridging oxygens of thymidine triphosphate (TTP) and 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) were replaced by a nitrogen, the resulting analogues were no longer substrates but instead became competitive inhibitors of HIV-1 RT.The most potent of the α,β-imidotriphosphate derivatives tested was thymidine 5'-triphosphate (TMPNPP, 1a).This analogue has a Ki value of 2.4 μM inhibiting HIV-1 RT 400-fold more potently than in inhibits DNA polymerase I large fragment (Klenow). 3'-Azido-3'-deoxythymidine 5'-triphosphate (AZTMPNPP, 1b) gave a Ki value about 10-fold greater than that for TMPNPP, indicating that a 3'-azido substituent decreases the affinity of AZTTP to HIV-1 RT relative to the normal 3'-OH substituent.Dideoxythymidine 5'-triphosphate (ddTMPNPP, 1c) was intermediate in potency, giving a Ki value of 15 μM.In contrast, substitution at the β,γ-bridging oxygen by nitrogen did not block the enzymatic cleavage of the adjacent α,β-phosphate linkage, and 3'-azidothymidine 5'-triphosphate (AZTMPPNP, 1e), the 5'-triphosphate analogue of AZTTP, is therefore both a substrate for and a potent inhibitor of HIV-1 RT with an observed Ki value of 87 nM.Further nitrogen substitution of the bridging oxygens in the phosphate chain decreases the inhibitory potency by approximately 10-fold as in the case of thymidine 5'-triphosphate (TMPNPNP, 1d).
