Synthesis and Characterization of DNA Minor Groove Binding Alkylating Agents
Synthesis and Characterization of DNA Minor Groove Binding Alkylating Agents
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DOI：
10.1021/tx300437x
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发表时间：
2013-01-01
影响因子：
4.1
通讯作者：
Gold, Barry
中科院分区：
文献类型：
--
作者：
Iyer, Prema;Srinivasan, Ajay;Gold, Barry
合成并表征了3-（1-甲基-5-（1-甲基-5-（丙基氨基甲酰基）-1H-吡咯-3-基氨基甲酰基）-1H-吡咯-3-基氨基）-3-氧代丙烷-1-磺酸甲酯（1）的衍生物。在所有情况下，N-末端附加有O-甲基磺酸酯，而C-末端基团随非极性和极性侧链而变化。此外，吡咯环的数目从2（二肽）到3（三肽）变化。证明了不同类似物有效产生N3-甲基腺嘌呤的能力，以及它们对小沟（N3-甲基腺嘌呤）相对于大沟（N7-甲基鸟嘌呤）甲基化的选择性。诱导圆二色性研究用于测量稳定砜类似物的DNA平衡结合性质;三肽结合的亲和力比二肽高>10倍。在alkA/tag糖基化酶突变体E.大肠杆菌和人WT神经胶质瘤细胞以及过表达和低表达N-甲基嘌呤-DNA糖基化酶的细胞中，所述糖基化酶从DNA中切除N3-甲基腺嘌呤。结果表明，平衡结合与产生的N3-甲基腺嘌呤水平和细胞毒性相关。1的毒性与MPG在细菌和哺乳动物细胞系中的表达呈负相关。增强的毒性与在MPG敲低细胞中观察到的PARP活化降低和醛反应位点形成速率降低平行。有人提出，未修复的N3-甲基腺嘌呤是有毒的，因为它能够直接阻断DNA聚合。
Derivatives of methyl 3-(1-methyl-5-(1-methyl-5-(propylcarbamoyl)-1H-pyrrol-3-ylcarbamoy1)-1H-pyrrol-3-ylamino)-3-oxopropane-1-sulfonate (1), a peptide-based DNA minor groove binding methylating agent, were synthesized and characterized. In all cases, the N-terminus was appended with an O-methyl sulfonate ester, while the C-terminus group was varied with nonpolar and polar side chains. In addition, the number of pyrrole rings was varied from 2 (dipeptide) to 3 (tripeptide). The ability of the different analogues to efficiently generate N3-methyladenine was demonstrated as was their selectivity for minor groove (N3-methyladenine) versus major groove (N7-methylguanine) methylation. Induced circular dichroism studies were used to measure the DNA equilibrium binding properties of the stable sulfone analogues; the tripeptide binds with affinity that is >10 fold higher than that of the dipeptide. The toxicities of the compounds were evaluated in alkA/tag glycosylase mutant E. coli and in human WT glioma cells and in cells overexpressing and under-expressing N-methylpurine-DNA glycosylase, which excises N3-methyladenine from DNA. The results show that equilibrium binding correlates with the levels of N3-methyladenine produced and cellular toxicity. The toxicity of 1 was inversely related to the expression of MPG in both the bacterial and mammalian cell lines. The enhanced toxicity parallels the reduced activation of PARP and the diminished rate of formation of aldehyde reactive sites observed in the MPG knockdown cells. It is proposed that unrepaired N3-methyladenine is toxic due to its ability to directly block DNA polymerization.