(+)-Negamycin, isolated from Streptomyces purpeofuscus, shows antimicrobial activity against Gram-negative bacteria and readthrough activity against nonsense mutations. Previously, we reported that two natural negamycin analogues, 5-deoxy-3-epi-negamycin and its leucine adduct, have more potent readthrough activity in eukaryocytes (COS-7 cells) than negamycin but possess no antimicrobial activity and no in vitro readthrough activity in prokaryotic systems. In the present study, on leucyl-3-epi-deoxynegamycin, a structure–activity relationship study was performed to develop more potent readthrough agents. In a cell-based readthrough assay, the derivative 13b with an o-bromobenzyl ester functions as a prodrug and exhibits a higher readthrough activity against TGA-type PTC than the aminoglycoside G418. This ester (13b) shows an in vivo readthrough activity with low toxicity, suggesting that it has the potential for treatment of hereditary diseases caused by nonsense mutations.

中文翻译：

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Leucyl-3- epi -deoxynegamycin对强力过早终止密码子通读的构效关系研究

从紫链霉菌中分离出的（+）-尼霉素显示出对革兰氏阴性菌的抗菌活性和对无意义突变的通读活性。以前，我们报道了两种天然的尼古霉素类似物5-deoxy-3- epi - negamycin及其亮氨酸加合物，在真核细胞（COS-7细胞）中的通读活性高于尼古霉素，但没有抗菌活性，也没有体外通读活性在原核系统中。在本研究中，对亮氨酰3-表皮-脱氧新霉素进行了结构-活性关系研究，以开发出更有效的通读剂。在基于细胞的通读分析中，衍生物13b带有o与氨基糖苷G418相比，β-溴苄基酯起着前药的作用，并且对TGA型PTC表现出更高的通读活性。该酯（13b）具有低毒性的体内通读活性，表明它具有治疗由无意义突变引起的遗传性疾病的潜力。