Abstract
The ultimate aim of the research described in this thesis was to synthesize biologically active vancomycin-inspired macrocyclic peptidomimetics. Previous research showed that both biaryl ether bridges in vancomycin can be mimicked by 1,5-disubstituted triazole moieties using the RuAAC macrocyclization. Although such bicyclic vancomycin CDE-ring mimics showed a relatively good structural
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resemblance with vancomycin, their binding affinity toward D-Ala-D-Ala is reduced 100-fold and antibacterial activity is absent. Several approaches were followed to explore possibilities to increase affinity and activity by either amino acid replacements, introduction of an extra cyclic constraint, or by a combination of these two. Chapter 2, describes the design and synthesis of a new CDE-ring mimic in which the amino acid was phenylglycine instead of leucine while an asparagine moiety was incorporated to foster binding interactions with the amide side chain and the carboxylate of the D-Ala-D-Ala/D-Ala-D-Lac dipeptide. However, it turned out that this attempt was unsuccessful since the new designed bicyclic mimic displayed almost the same binding affinity as before, and antibacterial activity could not be observed. Chapter 3 describes the solid phase synthesis of CDE-ring mimics as a more time-efficient synthesis approach. During the SPPS approach several difficulties were encountered since only three analogues were synthesized successfully. Unfortunately, the amounts obtained were too small for further analysis and biological evaluation. In hindsight, this chapter was focused to provide a proof-of-principle to access the bicyclic 1,5-triazole-bridged CDE-ring mimics of vancomycin. In Chapter 4, the bicyclic tripeptide as a mimic of the ABC-ring system was successfully synthesized following an RCM-coupling-RuAAC strategy. After RCM, the mixture of double bond isomers could be separated in each individual E/Z diastereoisomer by preparative HPLC. This tripeptide is an important building block for the synthesis of tricyclic hexapeptide in which the alkene bridge serves as an extra constraint to obtain a peptide backbone topology comparable to vancomycin. Chapter 5 describes the design and synthesis of a tricyclic hexapeptide in which the olefinic constraint was installed by RCM and both triazole bridges were synthesized featuring RuAAC. This hexapeptide represents a structure in which the ABC- and CDE-ring systems have been combined to adopt the concave-like conformation of the peptide backbone. Based on ITC measurements, the new designed mimic was able to bind D-Ala-D-Ala with an almost comparable affinity as vancomycin: 1.26×104 versus 4.23×105 M-1, the highest Ka found within this series of vancomycin mimics. Gratifyingly, in line with the results of the ITC measurements, this tricyclic mimic displayed antibacterial activity with a MIC value of 37.5 mg/mL while the MIC value of vancomycin was 2 mg/mL. This was the first time that a member of this class of vancomycin-inspired mimics showed a reasonable activity as an antimicrobial agent
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