Ostresh J M, Husar G M, Blondelle S E, Dörner B, Weber P A, Houghten R A
Torrey Pines Institute for Molecular Studies, San Diego, CA 92121.
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11138-42. doi: 10.1073/pnas.91.23.11138.
The generation of diverse chemical libraries using a "libraries from libraries" concept is described. The central features of the approaches presented are the use of well-established solid-phase synthesis methods for the generation of combinatorial libraries, combined with the chemical transformation of such libraries while they remain attached to the solid support. The chemical libraries that are generated by this process have very different physical, chemical, and biological properties compared to the libraries from which they were derived. A wide range of chemical transformations are possible for peptide-based or other libraries, and an almost unlimited range of useful chemical diversities can be envisioned. In the example presented, the amide functionalities in an existing combinatorial library made up of peptides were permethylated while the library remained attached to the solid-phase support used in its synthesis. After removal of the permethylated mixtures from their solid support, this library, now lacking the typical -CONH- amide bonds of peptides, can be tested in solution with virtually all existing assay systems to identify individual compounds having specific biological activities of interest. An illustration of the use of such libraries is presented, in which the described permethylated library was used to identify individual permethylated compounds having potent antimicrobial activity against Gram-positive bacteria.
本文描述了利用“库中库”概念生成多样化学文库的方法。所介绍方法的核心特点是使用成熟的固相合成方法来生成组合文库，并在文库仍连接于固相载体时对其进行化学转化。通过该过程生成的化学文库与衍生出它们的文库相比，具有非常不同的物理、化学和生物学性质。对于基于肽的文库或其他文库而言，多种化学转化是可行的，并且可以设想几乎无限范围的有用化学多样性。在给出的示例中，由肽组成的现有组合文库中的酰胺官能团在文库仍连接于其合成中使用的固相载体时进行了全甲基化。从固相载体上除去全甲基化混合物后，这个现在缺少肽典型的 -CONH- 酰胺键的文库可以在溶液中用几乎所有现有的分析系统进行测试，以鉴定具有特定感兴趣生物活性的单个化合物。文中给出了此类文库使用的一个示例，其中所述的全甲基化文库用于鉴定对革兰氏阳性细菌具有强效抗菌活性的单个全甲基化化合物。
