The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides

Cyclic peptides are appealing targets in the drug-discovery process. Unfort unately, there currently exist no robust solid-phase strategies that allow the synthesis of large arrays of discrete cyclic peptides. Existing strateg ies are complicated, when synthesizing large libraries, by the extensive wo rkup that is required to extract the cyclic product from the deprotection/c leavage mixture. To overcome this, we have developed a new safety-catch lin ker. The safety-catch concept described here involves the use of a protecte d catechol derivative in which one of the hydroxyls is masked with a benzyl group during peptide synthesis, thus making the linker deactivated to amin olysis. This masked derivative of the linker allows BOC solid-phase peptide assembly of the linear precursor. Prior to cyclization, the linker is acti vated and the linear peptide deprotected using conditions commonly employed (TFMSA), resulting in deprotected peptide attached to the activated form o f the linker. Scavengers and deprotection adducts are removed by simple was hing and filtration. Upon neutralization of the N-terminal amine, cyclizati on with concomitant cleavage from the resin yields the cyclic peptide in DM F solution. Workup is simple solvent removal. To exemplify this strategy, s everal cyclic peptides were synthesized targeted toward the somatostatin an d integrin receptors. From this initial study and to show the strength of t his method, we were able to synthesize a cyclic-peptide library containing over 400 members. This linker technology provides a new solid-phase avenue to access large arrays of cyclic peptides.