Balzarini J, Baba M, Pauwels R, Herdewijn P, De Clerq E
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Biochem Pharmacol. 1988 Jul 15;37(14):2847-56. doi: 10.1016/0006-2952(88)90049-4.
The 3'-fluoro-and 3'-azido-substituted derivatives of 2',3'-dideoxythymidine (ddThd), 2',3'-dideoxyuridine (ddUrd), 2',3'-dideoxy-5-ethyluridine (ddEtUrd) and 2',3'-dideoxycytidine (ddCyd) have been synthesized and evaluated for their anti-retrovirus activity [against human immunodeficiency virus (HIV) and murine Moloney sarcoma virus (MSV)]. Based on their 50% effective doses the most potent inhibitors of HIV replication in human MT4 lymphocytes were: FddThd (0.001 microM), AzddThd (0.004 microM), FddUrd (0.04 microM) and AzddUrd (0.36 microM). Their selectivity indexes were 197, 5000, 500 and 677, respectively. In contrast, none of the 3'-substituted ddEtUrd derivatives had a marked antiviral effect. The 2',3'-dideoxynucleoside analogues showed poor, if any, substrate affinity for (bacterial) dThd phosphorylase. AzddThd and FddThd inhibited human dThd kinase to a much greater extent (Ki/Km: 0.66 and 3.4, respectively) than did AzddUrd or FddUrd (Ki/Km: 71 and 171, respectively). The Ki/Km values of FddCyd and AzddCyd for human dCyd kinase were about 60. Although phosphorylation is a prerequisite for the anti-retrovirus activity of the 2',3'-dideoxynucleoside derivatives, there is no close correlation between the anti-retrovirus potency of the 3'-fluoro- and 3'-azido-substituted ddUrd, ddThd, ddEtUrd and ddCyd derivatives and their affinity for dThd kinase or dCyd kinase.
已合成了2′,3′-二脱氧胸苷（ddThd）、2′,3′-二脱氧尿苷（ddUrd）、2′,3′-二脱氧-5-乙基尿苷（ddEtUrd）和2′,3′-二脱氧胞苷（ddCyd）的3′-氟代和3′-叠氮基取代衍生物，并对其抗逆转录病毒活性[针对人类免疫缺陷病毒（HIV）和鼠莫洛尼肉瘤病毒（MSV）]进行了评估。根据其50%有效剂量，在人MT4淋巴细胞中最有效的HIV复制抑制剂为：FddThd（0.001微摩尔/升）、AzddThd（0.004微摩尔/升）、FddUrd（0.04微摩尔/升）和AzddUrd（0.36微摩尔/升）。它们的选择性指数分别为197、5000、500和677。相比之下，3′-取代的ddEtUrd衍生物均无明显抗病毒作用。2′,3′-二脱氧核苷类似物对（细菌）dThd磷酸化酶的底物亲和力很差（如果有的话）。AzddThd和FddThd对人dThd激酶的抑制作用比AzddUrd或FddUrd（Ki/Km分别为71和171）大得多（Ki/Km分别为0.66和3.4）。FddCyd和AzddCyd对人dCyd激酶的Ki/Km值约为60。尽管磷酸化是2′,3′-二脱氧核苷衍生物抗逆转录病毒活性的先决条件，但3′-氟代和3′-叠氮基取代的ddUrd、ddThd、ddEtUrd和ddCyd衍生物的抗逆转录病毒效力与其对dThd激酶或dCyd激酶的亲和力之间没有密切相关性。
