A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling.

A prerequisite for successful screening campaigns in drug discovery or chemical genetics is the availability of structurally and thus functionally diverse compound libraries. Diversity-oriented synthesis (DOS) provides strategies for the generation of such libraries, of which the build/couple/pair (B/C/P) algorithm is the most frequently used. We have developed an advanced B/C/P strategy that incorporates multidimensional coupling.

High-affinity multivalent wheat germ agglutinin ligands by one-pot click reaction.

A series of six mono-, di-, and trivalent N,N'-diacetylchitobiose derivatives was conveniently prepared by employing a one-pot procedure for Cu(II)-catalyzed diazo transfer and Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) starting from commercially available amines. These glycoclusters were probed for their binding potencies to the plant lectin wheat germ agglutinin (WGA) from Triticum vulgaris by an enzyme-linked lectin assay (ELLA) employing covalently immobilized N-acetylglucosamine (GlcNAc) as a reference ligand. IC(50) values were in the low micromolar/high nanomolar range, depending on the linker between the two disaccharides.

A two-directional strategy for the diversity-oriented synthesis of macrocyclic scaffolds.

Macrocyclic compounds represent a structural class with exceptional potential for biological activity; however, they have historically been underrepresented in screening collections and synthetic libraries. In this article we report the development of a highly step-efficient strategy for the diversity-oriented synthesis of complex macrocyclic architectures, using a modular approach based on the two-directional synthesis of bifunctional linear precursors and their subsequent combination in a two-directional macrocyclisation process. In this proof of principle study, the synthesis of 14 such compounds was achieved.

Preparation of carbohydrate arrays by using Diels-Alder reactions with inverse electron demand.

Carbohydrate microarrays are an emerging tool for the high-throughput screening of carbohydrate-protein interactions that represent the basis of many biologically and medicinally relevant processes. The crucial step in the preparation of carbohydrate arrays is the attachment of carbohydrate probes to the surface. We examined the Diels-Alder reaction with inverse-electron-demand (DARinv) as an irreversible, chemoselective ligation reaction for that purpose.

Diversity-oriented synthesis: producing chemical tools for dissecting biology.

Small molecule modulators of biological function can be discovered by the screening of compound libraries. However, it became apparent that some human disease related targets could not be addressed by the libraries commonly used which typically are comprised of large numbers of structurally similar compounds. The last decade has seen a paradigm shift in library construction, with particular emphasis now being placed on increasing a library's structural, and thus functional diversity, rather than only its size.

One-pot procedure for diazo transfer and azide-alkyne cycloaddition: triazole linkages from amines.

[reaction: see text] A one-pot reaction for Cu(II)-catalyzed diazo transfer and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (sometimes called click reaction) is reported. 1,4-Disubstituted 1,2,3-triazoles are obtained in excellent yields from a variety of readily available amines without the need for isolation of the azide intermediates. The reaction has a broad scope and is especially practical for the synthesis of multivalent structures because compounds substituted with multiple azides are potentially unstable.