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

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

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.

Abstract

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).

PMID:
1375962
DOI:
10.1021/jm00089a002
[Indexed for MEDLINE]

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