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

high dilution conditions. In continuation to our work with tetra-carbohydrazide cyclophanes, we
decided to study the dynamic reversibility of the macrocycles and the mechanism of the [2+2]-
cyclocondensation reaction. We also decided to assess the molecular recognition ability of tetracarbohydrazide
cyclophanes to a selection of oligopeptides unique in bacteria by ESI-TOF MS,
offering an innovative approach to the discovery of novel compounds with antibiotic activity.
Dynamic reversibility of tetra-carbohydrazide cyclophanes
Unlike conventional chemistry, dynamic combinatorial chemistry (DCC) is the field, in which
building blocks assemble to larger structures via reversibly formed covalent bonds. In DCC,
library members undergo continuous exchange until they reach an equilibration point, at which a
statistical mixture of all possible species has formed. Addition of an external trigger, usually a
guest molecule of interest, shifts equilibration to the most stable host guest complex and allows
its amplification. Despite its interesting features, only few applications of DCC in drug discovery
were reported. [31-34] Analysis of library members by ESI-MS shows considerable promise due to
the ability of this technique to provide precise mass values, high resolution and little or almost no
fragmentations. To realize DCCs, firstly the full reversibility of the reaction employed must be
demonstrated. Dynamic reversibility of tetra-carbohydrazide cyclophane formation was therefore
demonstrated by obtaining the same equilibrium composition of a mixture from two different
starting points of the reaction.
In a first crossover experiment, the macrocyclic precursors 1-4 were mixed in a mixture of
DMF/MeOH in presence of catalytic AcOH and the reaction was refluxed (path a). In a second
crossover experiment, we mixed equimolar amounts of macrocycles 5-7 in a mixture of
DMF/MeOH in presence of catalytic AcOH and the reaction was refluxed (path b). After eight
days the reaction reached the point of equilibrium, at which an almost identical statistical
mixture of macrocycles was obtained (Scheme 1). The macrocyclic library members appear in
the mass spectrum as both protonated and sodiated ions. ESI-TOF MS data for the products of
carbohydrazide exchange are shown in Table 1. (For ESI-TOF MS spectra at equilibration, see
Supporting Information). It is worth noting that the intensity of the peaks corresponding to the
characterised macrocycles can be plotted versus reaction time to provide a visual representation
of the composition of the dynamic library over the course of the reaction time as shown in Figure
1a and 1b.
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