Synthesis and biological evaluation of neamine analogues for RNA binding

新霉胺类似物的合成与RNA结合和生物活性评价(英文)

To design and synthesize neamine analogues modified at 5 position offing Ⅱ, which could improve the binding affinity of aminoglycosides to 16S RNA. Started from neomycin B, modified neamine analogues were synthesized through organic reactions such as hydrolysis, protection, nucleophilic substitution, deprotection and reduction. The interaction of the target compounds with A-site RNA in E. coli. ribosome （16S RNA） was determined by surface plasmon resonance （SPR）, respectively. Six target compounds were synthesized. Some of them showed antibacterial activities and enhanced affinity to 16S RNA at 10^-3M in vitro. Introduction amino or aliphatic amino group at 5 position offing Ⅱ in neamine would maintained antibacterial activities as well as increase binding affinity to 16S RNA. Furthermore, there is almost no influence on the stability of drug/16S RNA complex by inverting the configuration of 5-hydroxyl group at ring Ⅱ.

为了提高新霉胺对16S rRNA的亲和力,合成了Ⅱ环5位修饰的新霉胺类似物。以新霉素B为原料,经水解,保护,亲核取代,脱保护,叠氮还原多步反应得到氨基或氨基链修饰的新霉胺类似物。用表面等离子共振法测定了所合成的化合物与大肠杆菌(E.coli.)核糖体A位点rRNA(16S RNA)的相互作用。合成了6个Ⅱ环5-位修饰的新霉胺类似物,发现Ⅱ环5位氨基链修饰可以增强化合物对16S RNA的亲和力,其中一些化合物在10^(-3)M有体外细菌抑制活性。在新霉胺的Ⅱ环5位引入氨基或脂肪胺可以增加与16SRNA的亲和力。Ⅱ环5位上羟基的构型改变对于药物/16SRNA复合物稳定性的影响较低。