Garanger Elisabeth, Blois Joseph, Hilderbrand Scott A, Shao Fangwei, Josephson Lee
Laboratoire de Chimie des Polymeres Organiques (LCPO), UMR 5629 CNRS, IPB/ENSCBP, Universite Bordeaux I, Pessac Cedex, France.
J Comb Chem. 2010 Jan-Feb;12(1):57-64. doi: 10.1021/cc900141b.
Instead of using diversity oriented syntheses (DOS) to obtain compounds with biological activities, we employed the DOS method to efficiently obtain multifunctional single attachment point (MSAP) reagents for the conjugation to proteins. Acid insensitive functional groups (chelators, fluorochromes) were attached to Lys-Cys-NH(2) or Lys-Lys-betaAla-Cys-NH(2) peptide scaffolds. After cleavage from solid supports, the modified peptide intermediates were split and further modified by two solution phase, chemoselective reactions employing the single amine and single thiol presented on the intermediates. MSAP-based fluorochrome-chelates were obtained, some possessing a third functional group like a polyethylene glycol (PEG) polymer or "click chemistry" reactive alkynes and azides. The DOS of MSAP reagents permitted the efficient generation of panels of MSAP reagents that can be used to obtain multifunctional proteins with a single modified amino acid (a single attachment point).
我们并非使用面向多样性的合成方法（DOS）来获取具有生物活性的化合物，而是采用DOS方法高效地获得用于与蛋白质偶联的多功能单连接点（MSAP）试剂。将对酸不敏感的官能团（螯合剂、荧光染料）连接到Lys-Cys-NH(2)或Lys-Lys-βAla-Cys-NH(2)肽支架上。从固相载体上切割下来后，将修饰的肽中间体拆分，并通过利用中间体上存在的单胺和单硫醇进行的两个溶液相化学选择性反应进一步修饰。获得了基于MSAP的荧光染料-螯合剂，其中一些含有第三个官能团，如聚乙二醇（PEG）聚合物或“点击化学”反应性炔烃和叠氮化物。MSAP试剂的DOS允许高效生成一系列MSAP试剂，这些试剂可用于获得具有单个修饰氨基酸（单个连接点）的多功能蛋白质。
