The Development of Novel Antibiotics Using ... - Jacobs University

Scope of Work
Scope of Work
In this work the chemistry of trianglimine and tetra-carbohydrazide cyclophane macrocycles
have been utilized to generate DCLs in attempts to develop new macrocyclic receptors with
molecular recognition affinity to a selection of oligopeptides unique in bacteria. The difference
between human and bacterial cells is that the former completely lack a cell wall, while the later
die without an intact cell wall. This makes bacterial cell wall a versatile target for developing
new antibiotics. Bacteria make their cell wall from N-acetyl glucosamine and N-acetylmuramic
acid in a series of cross linking steps called transglycosylation and transpeptidation. Penicillin,
Bacitracin and Vancomycin act by causing disruption of the processes of cross linking and
inhibition of the carrier required for moving the building blocks of the cell wall across the
membrane. Vancomycin antibiotic binds D-Ala-D-Ala, which is an essential component forming
bacterial cell wall. Bacteria accomplished a resistance to Vancomycin by replacing the section
D-Ala-D-Ala with D-Ala-D-Lac. 1 The ability of Vancomycin to bind with D-Ala-D-Lac dramatically
reduced as a consequence of the elimination of a one hydrogen bond as illustrated in
Figure 3.1. DCC allows generation of structurally unique architectures, which cannot be obtained
by conventional synthesis. Trianglimines possess six imine bonds making them ideal candidates
for different DCC applications. 2 Trianglimines can be obtained in good quantities from commercially
available starting materials with complete control of the size of the central hole of the
macrocycles. 3,4 The cavity of the macrocycle itself can function as a good binding motif, while
the triangular side walls can be loaded with different functionalities, which can recognize and
bind with biological targets of interest. Aromatic dialdehyde 2 underwent successfully [3+3]-
cyclocondensation reaction with trans-(1R,2R)-1,2-diaminocyclohexane 3 to form a mixture of
regioisomeric C 3 -symmetrical 5 and non-symmetrical 6 trianglimines, which were separated by
column chromatography (CC) in high purity, but unfortunately in low yields (4-37%). 5 It is
noteworthy that compound 2 is an example of non-symmetrical dialdehydes, which was
synthesized using the Suzuki-coupling methodology of 4-bromo-2-substituted benzaldehyde and
4-formylphenyl boronic acid. Trianglimines underwent successfully dynamic exchange reactions
with generation of a DCL of interesting triangular architectures. 6 The major obstacles, however,
were the low yields of the macrocycles and the equilibration of the regioisomers in solution.
These obstacles would certainly render the assignment of the host, which forms the most stable
complex with the oligopeptide targets. In order to improve the yields of the macrocycles and to
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