Assessment of solution-phase positional scanning libraries based on distamycin A for the discovery of new DNA binding agents

The solution-phase synthesis of two 1000-membered positional scanning libra ries of distamycin A analogues is described enlisting acid/base liquid-liqu id extractions for isolation and purification of all intermediates and fina l products. The results of their screening for functional activity (L1210 c ytotoxic potency) and DNA binding affinity were compared with those derived from libraries containing the same compound members but prepared in a smal ler 10-compound mixture format. The positional scanning libraries, which ar e substantially less demanding to prepare, allowed the accurate detection o f the glob;ll 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 a nd the relative insensitivity of the assays to the contribution of any sing le, uniquely acting compound in the mixture. Thus, the disadvantages associ ated with the loss of some information contained within the library must be balanced against the advantages of the ease of library synthesis and judge d in light of the library screening objectives. (C) 2000 Elsevier Science L td. All rights reserved.