It is well known that the short half-life of peptides in vivo can be dramatically prolonged by chain-cyclization with a conformationally constrained feature. Compared to the disulfide bonding or amide bonding cydopeptides, an increasingly attraction in research on developing drug candidates is the design of unnatural structure hybridized cydopeptides. Herein, the first synthesis of Mannich base bridged cydopeptides by both solution-phase and solid-phase protocols is reported. Generally, aldehyde, amine and active-hydrogen component are the necessary building blocks for Mannich condensation. In present study, two of three Mannich's components, the /V-terminal aminogroup and the Tyr residure (served as the active hydrogen components) were assembled in the peptide substrate before reacting with the third component formalin, ensuring the formation of cyclo-Mannich base. As a result of the total yield (72.7%) of the product 10 from solid-phase protocol is much higher than the yield (5.38%) of product 5 from solution-phase procedure, the pseudo-dilution effect concerned with solid-phase should be responsible for the intrarmolecule condensation, avoiding from inter-molecule condensation. Therefore, present protocol would be a pragmatic way to prepare some unnatural structure hybridized cydopeptides.

Key words: MANNICH REACTION, CONDENSATION REACTION, cyclopeptide, SOLID PHASE REACTION