Boger D L, Dechantsreiter M A, Ishii T, Fink B E, Hedrick M P
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Bioorg Med Chem. 2000 Aug;8(8):2049-57. doi: 10.1016/s0968-0896(00)00137-1.
The solution-phase synthesis of two 1000-membered positional scanning libraries of distamycin A analogues is described enlisting acid/base liquid-liquid extractions for isolation and purification of all intermediates and final products. The results of their screening for functional activity (L1210 cytotoxic potency) and DNA binding affinity were compared with those derived from libraries containing the same compound members but prepared in a smaller 10-compound mixture format. The positional scanning libraries, which are substantially less demanding to prepare, allowed the accurate detection of the global observations and the clearly more potent activities, but more subtle discoveries and less distinguishable activities were not detected. This is a natural consequence of testing the larger 100-compound mixtures and the relative insensitivity of the assays to the contribution of any single, uniquely acting compound in the mixture. Thus, the disadvantages associated with the loss of some information contained within the library must be balanced against the advantages of the ease of library synthesis and judged in light of the library screening objectives.
本文描述了通过酸/碱液-液萃取法对放线菌素A类似物的两个1000成员的位置扫描文库进行溶液相合成，以分离和纯化所有中间体和最终产物。将它们的功能活性（L1210细胞毒性效力）和DNA结合亲和力筛选结果与来自相同化合物成员但以较小的10化合物混合物形式制备的文库的结果进行了比较。位置扫描文库的制备要求低得多，能够准确检测整体观察结果和明显更强的活性，但未检测到更细微的发现和难以区分的活性。这是测试较大的100化合物混合物以及该测定对混合物中任何单一独特作用化合物的贡献相对不敏感的自然结果。因此，与文库中某些信息丢失相关的缺点必须与文库合成容易的优点相权衡，并根据文库筛选目标进行判断。
