利奈唑胺治疗革兰氏阳性菌感染的临床成功与细菌核糖体的高度保守性相结合,预示着如果恶唑烷酮类药物被设计为在革兰氏阴性菌中积累,那么这一药理学类别将在根除感染方面具有广泛的用途。在这里,我们报告了一项针对战略设计的恶唑烷酮库的调查研究,以确定分子结构对积累和生物活性的影响。使用具有不同程度损害(外排和外膜)的大肠杆菌、鲍曼不动杆菌和铜绿假单胞菌菌株来鉴定阻碍跨外膜渗透和/或广泛且特异地在物种之间增强外排敏感性的基序。结果表明,分子结构的微小变化足以克服该支架的流出和/或渗透问题。鉴定出三种恶唑烷酮类似物( 3e 、 8d和8o ),它们对所评估的所有三种病原体均表现出活性,而利奈唑胺未观察到生物学特征。
Synthesis and Characterization of Cyclic Brush-Like Polymers by <i>N</i>-Heterocyclic Carbene-Mediated Zwitterionic Polymerization of <i>N</i>-Propargyl <i>N</i>-Carboxyanhydride and the Grafting-to Approach
作者:Samuel H. Lahasky、Wilson K. Serem、Li Guo、Jayne C. Garno、Donghui Zhang
DOI:10.1021/ma201948u
日期:2011.12.13
Cyclic brush-like polymers were synthesized by tandem organo-mediated zwitterionic polymerization and a grafting-to approach. The cyclic polymer backbone, consisting of poly(N-propargylglycine) (c-PNPG), was synthesized by an N-heterocyclic carbene (NHC)-mediated zwitterionic ring-opening polymerization of N-propargyl N-carboxyanhydride. The polymerization proceeds in a quasi-living manner, allowing access to c-PNPG of well-defined chain length. The cyclic architecture of the polymers was verified by size exclusion chromatography (SEC) and mass spectroscopy (MS), as well as scanning probe characterization. Poly(ethylene glycol) functionalized with azido end-groups was subsequently grafted onto the c-PNPG by the copper-mediated azide/alkyne cycloaddition reaction (CuAAC). The side chain grafting density was determined by H-1 NNIR spectroscopy and SEC analysis. The grafting efficiency is low (<19%) when the cyclic backbone is comprised of a c-PNPG homopolymer. The efficiency can be significantly improved (up to 93%) by utilizing cyclic poly(N-propargylglycine)-ran-poly(N-butylglycine) random copolymers (c-PNPG-r-PNBG). This has been attributed to the ease of access to the propargyl groups in c-PNPG and c-PNPG-ran-PNBG: the strong tendency of the former to aggregate in common organic solvents (including the CuAAC reaction medium) restricts access to the propargyl groups.