Activity of acyclic halogenated tubercidin analogs against human cytomegalovirus and in uninfected cells.
Activity of acyclic halogenated tubercidin analogs against human cytomegalovirus and in uninfected cells.
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无环卤化结核菌素类似物对抗人巨细胞病毒和未感染细胞的活性。
DOI：
10.1016/0166-3542(91)90020-r
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发表时间：
1991
影响因子：
7.6
通讯作者：
Drach,JC
中科院分区：
文献类型：
--
作者：
Nassiri,MR;Turk,SR;Birch,GM;Coleman,LA;Hudson,JL;Pudlo,JS;Townsend,LB;Drach,JC
在减产试验中，研究了新型无环卤化杀瘤素(4-amino-5-halo-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2，3-d]pyrimidines)对人巨细胞病毒的抑制作用。与氯和碘取代的类似物(化合物100和104)相比，5-溴无环结核杀菌素(化合物102)对病毒复制的抑制作用更强。在100μM浓度下，溴和氯化合物的药效比阿昔洛韦强，但不比更昔洛韦强。化合物102和104使病毒滴度降低了99%以上，而化合物100和同等效力的阿昔洛韦仅使病毒滴度降低了90%。DNA杂交定量检测表明，这些化合物对人巨细胞病毒DNA合成有较强的抑制作用。最有效的抑制剂化合物102的半数抑制浓度(I50)为1.6μM，与更昔洛韦相当(1.8μM)。对未感染的人细胞进行了细胞毒性实验，结果表明：在10μM化合物102存在下，细胞生长速度显著减慢，而相同浓度的化合物100和104仅使群体倍增时间略有延长；通过将放射性标记的前体掺入可酸沉淀的大分子中，这些化合物抑制了细胞的DNA合成，但不抑制RNA或蛋白质的合成；流式细胞仪检测表明，化合物102是S中期的阻滞剂，腺苷可拮抗化合物102对[~3H]dThd掺入的抑制。总之，这些结果表明，化合物102是一种有效的和选择性的病毒和细胞DNA合成的抑制剂，非环卤代吡咯嘧啶核苷可能具有治疗潜力。
Novel acyclic halogenated tubercidins (4-amino-5-halo-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidines) were examined for their ability to inhibit human cytomegalovirus (HCMV) in yield reduction assays. 5-Bromo acyclic tubercidin (compound 102) was a more potent inhibitor of virus replication than the chloro- and iodo-substituted analogs (compounds 100 and 104). At a 100 μM concentration, the bromo and chloro compounds were more potent than acyclovir but not ganciclovir. Virus titers were reduced more than 99% by compounds 102 and 104 whereas compound 100 and the equally potent acyclovir reduced titers by only 90%. Quantitation of viral DNA by DNA hybridization demonstrated strong inhibition of HCMV DNA synthesis by these compounds. The most potent inhibitor, compound 102, had a 50% inhibitory (I50) concentration (1.6 μM) comparable to that of ganciclovir (1.8 μM). Cytotoxicity in uninfected human cells was evaluated and revealed the following: cell growth rates slowed markedly in the presence of 10 μM compound 102 whereas the same concentration of compounds 100 and 104 led to only a slight prolongation of population doubling time; these compounds inhibited cellular DNA synthesis but not RNA or protein synthesis, as measured by incorporation of radiolabeled precursors into acid-precipitable macromolecules; flow cytometry indicated that compound 102 was a mid-S phase blocker, and adenosine antagonized the inhibition of [3H]dThd incorporation by compound 102. Together, these results demonstrate that compound 102 is a potent and selective inhibitor of viral and cellular DNA synthesis and that acyclic halogenated pyrrolopyrimidine nucleosides may have therapeutic potential.