Biomedical subjects
Publications and source records attributed to S R Klopfenstein.
Lead compounds with the potential to progress to viable drug candidates have been identified from libraries using several strategies. These include rapid screening of large diverse collections, thematic libraries, project-directed libraries, and three-dimensional molecular models of corporate databases. There have been numerous success stories, including the identification of several clinical candidates.
This article is a subjective review of the literature from 1999 to March 2001. It seeks to highlight current progress in the high-throughput synthesis of peptide mimetics. The review is loosely classified into sections based on the type of secondary structural feature which is being mimicked (reverse turn, beta-strand, peptide surrogates) or a common motif. The examples chosen have demonstrated the ability to produce a large number of compounds rapidly or, in our opinion, the method could produce large numbers of compounds if desired.
[structure: see text]The solid-supported synthesis of a bicyclic diketopiperazine, a potential peptide beta-turn mimetic, is described. The Ugi reaction between the resin ester of alpha-N-Boc-diaminopropionic acid (an amine input), alpha-bromo acid, aldehyde, and isocyanide is the key step in the proposed protocol.
An automated high-throughput liquid-liquid extraction (LLE) methodology has been developed and utilized for the initial purification of the combinatorial library samples containing unreacted amines and other water-soluble byproducts or impurities. Various extraction solvents were evaluated along with different extraction devices. The LLE method was automated using 96-well-format plates and a robotic liquid-handling workstation. In the optimized LLE method, crude combinatorial library samples were dissolved in a water-immiscible organic solvent, butyl acetate, and added to each well in a 96-well-format plate packed with an inert support material coated with hydrochloric acid. Separation occurs based on the partitioning of the compounds between two liquid phases. Product recovery, purity, and amine removal efficiency were determined by HPLC with and without precolumn derivatization. The automated method was successfully applied to the cleanup of some representative combinatorial library samples with greater than 98% amine removal and an average product purity of 90%. The application of the automated high-throughput LLE method should greatly reduce the labor, time, and cost associated with the purification of combinatorial libraries.