Figure B) High pressure liquid chromatography (HPLC) of a crude product after cleavage from the support.


So far, synthesis of diketopiperazines (58), hydantoines, triazines, benzimidazoles and quinoxalines were evaluated. Such libraries will be further advanced by continuously incorporating other types of chemical and enzymatic reactions (14) and by implementing synthetic routes as developed in the Department of “Medicinal Chemistry of Antiinfectives” for natural-product-born structures that are being discovered in the microbial metabolite screening program of the Chemical Pipeline. Improvements of the solid-phase chemistry to expand the scope of applications and adaptations to screening processes are other topics of our synthetic work: novel linkers to prepare tagged or immobilized cyclic peptides; linkers for in situ release of compounds into aqueous media (Frank-Linker, product of IRIS Biotech GmbH) to be used in continuous format screening (CFS), see below.

Combinatorial Chemical Synthesis

R. Frank, D. Koska, V. Wächter, S. Daenicke, D. Oster, E. Schmeisser, S. Thiele

As depicted in Figure A, for the stepwise chemical assembly of our compound libraries we exclusively apply solid-phase synthesis and carry out the coupling of small building blocks (monomers) as well as mixtures of these (pools). The starting monomers are anchored to the solid support either via a stable linker to yield covalent attached products or via a cleavable linker to allow release of the product into solution. Coupling efficiencies are optimized with a series of model syntheses to yield crude products of >90% purity (Figure B). In this way, mo-lecular libraries of several thousand and up to several billion compounds can be quickly syn-thesized for screening in biological assays in the form of support-bound or soluble products.

Combinatorial chemical synthesis

Figure A) Stepwise assembly of a diketopiperazine by coupling an amino acid (1), chloroacetic acid (2), an amino acid methyl ester (3), chloracetic acid (4), and an amine (5) followed by in situ cyclization.


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