Ma Q F, Bathurst I C, Barr P J, Kenyon G L
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
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).
已经合成了几种新型的胸苷亚氨基三磷酸类似物，并已证明它们是人类免疫缺陷病毒1逆转录酶（HIV-1 RT）的有效抑制剂。当胸苷三磷酸（TTP）和3'-叠氮基-3'-脱氧胸苷5'-三磷酸（AZTTP）的α，β-桥连氧被氮取代时，所得类似物不再是底物，而是成为HIV-1 RT的竞争性抑制剂。测试的最有效的α，β-亚氨基三磷酸衍生物是胸苷5'-[α，β-亚氨基]三磷酸（TMPNPP，1a）。该类似物的Ki值为2.4μM，抑制HIV-1 RT的效力比抑制DNA聚合酶I大片段（Klenow）强400倍。3'-叠氮基-3'-脱氧胸苷5'-[α，β-亚氨基]三磷酸（AZTMPNPP，1b）的Ki值比TMPNPP大约高10倍，表明相对于正常的3'-OH取代基，3'-叠氮基取代基降低了AZTTP对HIV-1 RT的亲和力。双脱氧胸苷5'-[α，β-亚氨基]三磷酸（ddTMPNPP，1c）的效力处于中间水平，Ki值为15μM。相比之下，β，γ-桥连氧被氮取代不会阻断相邻α，β-磷酸键的酶促裂解，因此3'-叠氮胸苷5'-[β，γ-亚氨基]三磷酸（AZTMPPNP，1e），AZTTP的5'-[β，γ-亚氨基]三磷酸类似物，既是HIV-1 RT的底物又是强效抑制剂，观察到的Ki值为87 nM。磷酸链中桥连氧的进一步氮取代使抑制效力降低约10倍，如胸苷5'-[α，β：β，γ-二亚氨基]三磷酸（TMPNPNP，1d）的情况。
