Synthesis of Triazole Bridged Vancomycin Mimics

Abstract

Cyclic peptides are an important class of compounds with broad biological activities. Both natural as well as synthetic cyclic peptides have been recognized as a great resource and inspiration for drug discovery. Macrocyclization is recognized as an efficient way to restrict the conformational freedom of a peptide which often leads to increased affinity and selectivity. However, only a limited number of approaches for efficient peptide macrocyclization are presently available. Vancomycin is the most representative member of a family of glycopeptide antibiotics, which are the most important class of drugs for the treatment of resistant bacterial infections. The ongoing development of novel synthetic methodology to access conformationally restricted cyclic peptides encouraged us to develop effective approaches to mimic the bioactive conformation of vancomycin as closely as possible. This thesis describes the application of CuAAC and RuAAC macrocyclization for the synthesis of vancomycin mimics. The synthesis of cyclic 1,4-triazole-bridged tripeptides as vancomycin DE-ring mimics was described. Based on the successful synthesis of a series of linear tripeptides functionalized with alkyne and azide groups, the macrocyclization using CuAAC chemistry was successfully achieved. With the TBTA-promoted CuAAC macrocyclization strategy, two cyclic monomeric tripeptides, derived from ornithine and lysine, were successfully synthesized. As a relevant follow-up study after the successful application of CuAAC for the synthesis of the vancomycin DE-ring mimics, a RuAAC click-type macrocyclization protocol described, and a series of cyclic 1,5-triazole-bridged tripeptides as vancomycin DE-ring mimics was synthesized in good yield. The most constrained cyclic tripeptide obtained had only 13 atoms in the macrocyclic ring, while the lysine-derived tripeptide was of the same size as the vancomycin DE-ring containing 16 atoms. The RuAAC macrocyclization proved to be effective for the synthesis of 1,5-disubstituted triazole-containing cyclic tripeptides, and was superior compared to the CuAAC-based click cyclization with respect to the prevalent synthesis of monomeric cyclic peptides. With the successful application of the RuAAC macrocyclization for the synthesis of the DE-ring mimics of vancomycin, the synthesis of 1,5-triazole-bridged bicyclic vancomycin CDE-ring peptidomimetic using RuAAC macrocyclization was successfully achieved. The synthesis of a linear hexapeptide functionalized with alkyne and azide groups was carefully optimized and the synthesis could be accomplished within 10 steps with good to excellent yield. The RuAAC macrocyclization was successfully developed to synthesize the 1,5-triazole-bridged bicyclic peptidomimetic. The antibacterial activity of the synthesized bicyclic compound was investigated, but no obvious inhibition of the bacterial growth was observed. In general, the investigation as described in this thesis showed the successful application of CuAAC and RuAAC macrocyclization strategy for the synthesis of vancomycin DE- and CDE-ring mimics. Especially, the RuAAC chemistry turned out to be a very efficient strategy for the synthesis of small cyclic peptides with excellent intramolecular selectivity. Although the synthesized peptidomimetics were not biologically active, the methodology developed here could be applied for the structural optimization of cyclic peptides that lead to biologically interesting targets.