A Dual Photochemical Ring-Opening/Cleavage Approach for the Synthesis and Decoding of One-Bead-One-Compound Cyclic Peptide Libraries

摘要

With a great therapeutic potential, peptide macrocycles have gained a lot of interest in drug discovery. Compared to their linear counterparts, cyclic peptides show improved resistance to proteases and their increased conformational rigidity lowers the entropic cost of binding, making them tighter-binding to a given macromolecule [1,2]. The great degree of molecular diversity and complexity that can be accessed by simple changes in their sequence has prompted the use of cyclic peptides in combinatorial chemistry. The one-bead-one-compound (OBOC) approach, in which each bead carries many copies of a unique compound, has become a powerful tool in the drug discovery process [3]. However, the use of cyclic peptides in combinatorial OBOC libraries has been limited by difficulties in sequencing hit compounds after the screening. Lacking a free N-terminal amine, Edman degradation sequencing cannot be used on cyclic peptides and complicated fragmentation patterns are obtained by tandem mass spectrometry (MS/MS). This problem has been initially overcome by using a bead topological segregation strategy [4,5]. More recently, different strategies have been reported to avoid encoding by using a ring-opening approach to allow a simultaneous linearization and compound release from the bead [6-9]. Most of the reported methods require post-screening chemical reactions that could lead to side chain modification. Based on these strategies, we were looking for an efficient, single step and chemical reagent free ring-opening approach that would be compatible with free amino acid side chains.