Nucleic Acid Center, University of Southern Denmark, 5230 Odense M, Denmark.
J Med Chem. 2012 Mar 8;55(5):2067-77. doi: 10.1021/jm201266b. Epub 2012 Feb 16.
Pleuromutilin is an antibiotic that binds to bacterial ribosomes and thereby inhibit protein synthesis. A new series of semisynthetic pleuromutilin derivatives were synthesized by a click chemistry strategy. Pleuromutilin was conjugated by different linkers to a nucleobase, nucleoside, or phenyl group, as a side-chain extension at the C22 position of pleuromutilin. The linkers were designed on the basis of the best linker from our first series of pleuromutilin derivatives following either conformational restriction or an isosteric methylene to oxygen exchange. The binding of the new compounds to the Escherichia coli ribosome was investigated by molecular modeling and chemical footprinting of nucleotide U2506, and it was found that all the derivatives bind to the specific site and most of them better than pleuromutilin itself. The effect of the side-chain extension was also explored by chemical footprinting of nucleotide U2585, and the results showed that all the compounds interact with this position to varying degrees. Derivatives with a conformational restriction of the linker generally had a higher affinity than derivatives with an isosteric exchange of one of the carbons in the linker with a hydrophilic oxygen. A growth inhibition assay with three different bacterial strains showed significant activity of several of the new compounds.
截短侧耳素是一种抗生素，它与细菌核糖体结合，从而抑制蛋白质合成。通过点击化学策略，合成了一系列新的半合成截短侧耳素衍生物。截短侧耳素通过不同的连接子与碱基、核苷或苯基连接，作为截短侧耳素 C22 位的侧链延伸。这些连接子是基于我们的第一系列截短侧耳素衍生物中最好的连接子设计的，要么是构象限制，要么是等排的亚甲基到氧交换。通过分子建模和核苷酸 U2506 的化学足迹研究了新化合物与大肠杆菌核糖体的结合情况，发现所有衍生物都结合到特定的位点，其中大多数比截短侧耳素本身结合得更好。通过核苷酸 U2585 的化学足迹研究还探索了侧链延伸的效果，结果表明所有化合物都在不同程度上与该位置相互作用。具有连接子构象限制的衍生物通常比具有连接子中一个碳原子与亲水性氧等排交换的衍生物具有更高的亲和力。对三种不同细菌菌株的生长抑制试验表明，几种新化合物具有显著的活性。
