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

ability of the technique to provide precise mass values, high
resolution and little or almost no fragmentations make it an
indispensable tool in supramolecular analysis. After successful
synthesis and characterisation of tetra-(hydrazinecarboxamide)
cyclophanes 5-10, we decided to carry out a preliminary qualitative
assessment of their recognition ability in the gas phase to a wide
variety of chiral carboxylic acids, amino acids and oligopeptides of
biological interest (Scheme 1). Macrocycles 7 and 8 were chosen
for the complexation study. ESI-TOF/MS was used to provide
information about high resolution m/z values of the screened
host/guest complexes, while tandem MS was used for further confirmation
of complexation by means of fragmentation.
Oligopeptides AcNH-D-Ala-D-Glu-L-Lys-D-Ala-D-Ala-Gly-
COOH 15, AcNH-D-Glu-L-Lys-D-Ala-D-Ala-Gly-COOH 16 and
AcNH-L-Lys-D-Ala-D-Ala-Gly-COOH 17 which mimic bacterial
cell wall structure were chosen for the recognition study and were
synthesised using solid phase peptide syntheses using the Fmoc
method. The purity and identity of 15-17 were assessed by HPLCtandem
MS. Equimolar quantities of host 7 or 8 and guests 11-17
were used. To the host/guest mixture 5 µL of DMF (N,N-dimethylformamide)
and H 2 O were added, sample was diluted with 1 mL of
ACN (Acetonitrile) and well sonicated prior to direct injection into
the ESI-TOF mass spectrometer. It can be inferred that macrocycles
7 and 8 showed promising recognition affinity in the gas
phase to the chosen guests 11-17. A stoichiometry of 1:1 host/guest
complex was observed by ESI-MS which did not change by adding
more equivalents of the guest molecules. As a general observation
we found that the peak intensity of the screened host/guest
complex increases by increasing the number of carboxylic motifs
(COOH) in the guest molecule. Thus, host/guest complex 7/13
showed higher peak intensity in comparison with 7/11. Also, guests
11 and 13 showed the highest peak intensities in comparison with
the rest of the screened compounds shown in Scheme 1. At a
competitive level, host 7 binds prefrentially to guest 13 in a
mixture of 7 with guests 11 and 13. ESI-TOF/MS and tandem MS
for host/guest complex 7/13 are shown in Figure 7.
Figure. 4 Computed structures and conformation of tetra-(hydrazinecarboxamide)
cyclophanes 5 at the MM+ level. A Polak-Ribiere conjugate gradient
with rms ˂ 0.01 Kcal.mol –1 was used.
Figure 6. Computed structure for intermediate B at the MM+ level. A
Polak-Ribiere conjugate gradient with rms ˂ 0.01 Kcal.mol –1 was used.
Figure 5. 2D ROESY spectrum for macrocycle 5.
Scheme 1. Chiral guests 11-17 which have been recognised in the gas phase
by hosts 7 and 8.
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