Facile Synthesis of Homodimeric Protein Ligands

Bivalent ligands can engage homodimeric protein targets with high affinity due to avidity effects. This study shows that compounds conjugated to a masked formyl acetamide can be coupled efficiently and conveniently through trifluoroacetic acid (TFA)-catalyzed pyridone formation. In most cases, the product is produced in nearly quantitative yield and in excellent purity. The reaction is tolerant of a wide range of functional groups.

Abstract

Many proteins exist as oligomers (homodimers, homotrimers, etc.). A proven strategy for the development of high affinity ligands for such targets is to link together two modest affinity ligands that allows the formation of a 2 : 2 (or higher-order) protein-ligand complex. We report here the discovery of a convenient, “click-like” reaction for the homodimerization of protein ligands that is efficient, operationally simple to carry out, and tolerant of many functional groups. This chemistry reduces the synthetic burden inherent in the creation of homodimeric ligands since only a single precursor is required. The utility of this strategy is demonstrated by the synthesis of homodimeric inhibitors, including PROTACs.

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