Application of a photolabile backbone amide linker for cleavage of internal amides in the synthesis towards melanocortin subtype-4 agonists

A new photolabile backbone amide handle has been developed for the synthesis of a melanocortin subtype-4 receptor (MCR4) agonist library in the solid phase. This traceless linker allows for the solid-supported synthesis of internal amides and their release under very mild, orthogonal conditions from solid support. The chemistry to attach an amide onto the linker is discussed. Structural variations of the linker in order to facilitate the attachment are investigated. The cleavage rate on the solid phase was measured. Finally, a small arylpiperazine library towards the MCR4 receptor was synthesized and its members characterized via HPLC, MS and NMR.