New thymidine triphosphate analogue inhibitors of human immunodeficiency virus-1 reverse transcriptase

J Med Chem. 1992 May 29;35(11):1938-41. doi: 10.1021/jm00089a002.


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 alpha,beta-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 alpha,beta-imidotriphosphate derivatives tested was thymidine 5'-[alpha,beta-imido]triphosphate (TMPNPP, 1a). This analogue has a Ki value of 2.4 microM, inhibiting HIV-1 RT 400-fold more potently than it inhibits DNA polymerase I large fragment (Klenow). 3'-Azido-3'-deoxythymidine 5'-[alpha,beta-imido]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'-[alpha,beta-imido]triphosphate (ddTMPNPP, 1c) was intermediate in potency, giving a Ki value of 15 microM. In contrast, substitution at the beta,gamma-bridging oxygen by nitrogen did not block the enzymatic cleavage of the adjacent alpha,beta-phosphate linkage, and 3'-azidothymidine 5'-[beta,gamma-imido]triphosphate (AZTMPPNP, 1e), the 5'-[beta,gamma-imido]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'-[alpha,beta:beta,gamma-diimido]triphosphate (TMPNPNP, 1d).

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding, Competitive
  • Dideoxynucleotides
  • HIV-1 / enzymology*
  • Molecular Structure
  • RNA-Directed DNA Polymerase / metabolism
  • Reverse Transcriptase Inhibitors*
  • Structure-Activity Relationship
  • Thymine Nucleotides / chemical synthesis
  • Thymine Nucleotides / chemistry*
  • Thymine Nucleotides / metabolism
  • Thymine Nucleotides / pharmacology*
  • Zidovudine / analogs & derivatives*
  • Zidovudine / chemical synthesis
  • Zidovudine / metabolism
  • Zidovudine / pharmacology


  • Dideoxynucleotides
  • Reverse Transcriptase Inhibitors
  • Thymine Nucleotides
  • thymidine 5'-(alpha,beta-imido)triphosphate
  • 3'-azido-3'-deoxythymidine 5'-(beta,gamma-imido)triphosphate
  • Zidovudine
  • RNA-Directed DNA Polymerase
  • thymidine 5'-triphosphate