Rapid synthesis and screening of compound libraries enables the accelerated identification of novel protein ligands in order to support processes like analysis of protein interactions, drug target discovery or lead structure discovery. SPOT synthesis—a well established method for the rapid preparation of peptide arrays—has recently been extended to the field of nonpeptides. In this contribution we report on the systematic evaluation of the SPOT technique for the assembly of N-alkylglycine (peptoid) library arrays. In the course of this investigation bromoacetic acid 2,4-dinitrophenylester (1a) was identified to be the most suited agent for bromoacetylation in terms of yield and N-selectivity enabling straightforward submonomer synthesis on hydroxy-group rich cellulose membranes. The potential of this method for the rapid identification of novel nonpeptidic protein ligands was demonstrated by synthesis and screening of a library consisting of 8000 peptoids and peptomers (i.e. their hybrids with α-substituted amino acids) allowing the identification of micromolar ligands for the monoclonal antibody Tab-2.

This report describes the development of an efficient solid-phase synthesis protocol and adaptation of reported solution phase procedures for the synthesis of the cyclic depsihexapeptide destruxin A and related analogs. The solid-phase method described is based on standard Fmoc peptide chemistry, including a new synthetic method for the assembly of the depsi bond-containing unit. In order to select analogs of destruxin A for synthesis and evaluation of insecticidal activity, the work of Hellberg et al., describing a set of Z-descriptors for amino acid side-chains comparing their physicochemical properties, was utilized. Destruxin A and 27 different analogs with structural variations in four residues were synthesized and insecticidal activity was evaluated via injections into tobacco budworm (Heliothis virescens) larvae. Several destruxin A analogs were found to be at least as potent as the native compound.

Combinatorial chemistry is well suited for the rapid and systematic optimization of molecular properties. The approach is commonly used for the generation of large numbers of compounds which can be applied for the examination of novel materials, catalysts or receptors. However, most frequently assembly of compound libaries is directed to the identification and optimization of novel therapeutic leads to accelerate the drug discovery process. The majority of combinatorial libraries assembled so far was synthesized on solid supports. The advantages of this method are the opportunity to use excesses of reagents driving reactions to completion and the fact that several technologies were invented to automatize and miniaturize these reactions. Beside high throughput parallel synthesis on resin beads, polymeric pins and chips [1], SPOT-synthesis using continuous membranes has been described to be an efficient synthetic approach [2]. The major feature of the latter method is the positionally addressed delivery of small volumes of liquids to a membrane surface. The droplets dispensed by a robot form separate spots which can be considered as micro-reactors provided that a non-volatile solvent system is used (Fig. 1).