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

Paper 5 Rapid Commu. Mass Spectrom., 2012, accepted manuscript
Probing the dynamic reversibility and generation of dynamic combinatorial
libraries in the presence of bacterial model oligopeptides
as templating guests of tetra-carbohydrazide macrocycles using electrospray
mass spectrometry
Hany F. Nour, Tuhidul Islam, Marcelo Fernández-Lahore and Nikolai Kuhnert*
Objectives of the work
Functionalized tetra-carbohydrazide cyclophanes were successfully synthesized in excellent yields
following the previously discussed approaches. The first objective of this work is to confirm the
dynamic reversibility of the novel macrocycles. Two crossover experiments were conducted in order to
prove the dynamic reversibility of tetra-carbohydrazide cyclophanes. In the first crossover experiment,
three different pure macrocycles were mixed in a mixture of DMF/MeOH in presence of catalytic
AcOH and the reaction was refluxed. In the second crossover experiment, the macrocyclic precursors
were mixed in a mixture of DMF/MeOH in presence of catalytic AcOH and the reaction was refluxed.
After eight days of reflux, the reaction reached the point of equilibrium, at which an almost identical
statistical mixture of macrocycles was obtained. The second objective is to generate a DCL of tetracarbohydrazide
cyclophanes in which the members possess more polar functionalities. Introducing
such functionalities is expected to reinforce binding with biological guests. A DCL of eight highly
functionalized cyclophane macrocycles was generated in solution by mixing two different dihydrazides
with two different dialdehydes. The composition of the DCL was screened by ESI-TOF/MS and the
molecular ion peaks for all expected members were observed and assigned based on their high
resolution m/z values. Three members in the dynamic library showed recognition in the gas phase to a
selection of oligopeptides which mimic bacterial cell wall structure.
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