Mei Hui, Xing Lei, Cai Li, Jin Hong-Wei, Zhao Peng, Yang Zhen-Jun, Zhang Liang-Ren, Zhang Li-He
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road #38, Beijing 100083, China.
Bioorg Med Chem Lett. 2008 Oct 15;18(20):5355-8. doi: 10.1016/j.bmcl.2008.09.062. Epub 2008 Sep 19.
Two types of neamine derivatives, neamine-dinucleotide conjugates 8a-g and neamine-PNA conjugates 12a-c and 14a-d, were synthesized. Compound 8a-g were synthesized by the condensation of azido-neamine with dinucleotide-5'-carboxylic acids, followed by reduction and deprotection. Compound 12a-c and 14a-d were synthesized by the similar strategy. The binding affinities of conjugates 8a-g, 12a-c, and 14a-d towards 16S RNA, 18S RNA, and TAR RNA were evaluated by SPR. It indicates that conjugates 12a-c and 14a-d interact with 16S, 18S RNA at the same level as that of neamine, 14a and 14d show about twofold binding affinities to TAR RNA compared to that of neamine. However, the neamine-dinucleotide conjugates 8a-g exhibit very weak binding affinities to 16S, 18S, and TAR RNA, computer modelling results that negative-negative electrostatic repulsion of phosphate group in compound 8a-g and RNA leads to a sharp decrease of the binding affinities compared with that of neamine, neamine-nucleoside and neamine-PNA conjugates.
合成了两种新霉素衍生物，即新霉素 - 二核苷酸缀合物8a - g和新霉素 - PNA缀合物12a - c以及14a - d。化合物8a - g通过叠氮基新霉素与二核苷酸 - 5'-羧酸缩合，然后还原和脱保护来合成。化合物12a - c和14a - d通过类似策略合成。通过表面等离子体共振（SPR）评估缀合物8a - g、12a - c和14a - d对16S RNA、18S RNA和TAR RNA的结合亲和力。结果表明，缀合物12a - c和14a - d与16S、18S RNA的相互作用水平与新霉素相同，14a和14d对TAR RNA的结合亲和力比新霉素高约两倍。然而，新霉素 - 二核苷酸缀合物8a - g对16S、18S和TAR RNA表现出非常弱的结合亲和力，计算机模拟结果表明，与新霉素、新霉素 - 核苷和新霉素 - PNA缀合物相比，化合物8a - g中的磷酸基团与RNA之间的负 - 负静电排斥导致结合亲和力急剧下降。
