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
Article first published online: 7 NOV 2012
Copyright © 2012 John Wiley & Sons, Ltd.
Rapid Communications in Mass Spectrometry
Volume 26, Issue 24, pages 2865–2876, 30 December 2012
How to Cite
Nour, H. F., Islam, T., Fernández-Lahore, M. and Kuhnert, N. (2012), 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. Rapid Commun. Mass Spectrom., 26: 2865–2876. doi: 10.1002/rcm.6401
- Issue published online: 5 NOV 2012
- Article first published online: 7 NOV 2012
- Manuscript Accepted: 9 SEP 2012
- Manuscript Revised: 7 SEP 2012
- Manuscript Received: 7 JUN 2012
Over the past few decades, bacterial resistance to antibiotics has emerged as a real threat to human health. Accordingly, there is an urgent demand for the development of innovative strategies for discovering new antibiotics. We present the first use of tetra-carbohydrazide cyclophane macrocycles in dynamic combinatorial chemistry (DCC) and molecular recognition as chiral hosts binding oligopeptides, which mimic bacterial cell wall. This study introduces an innovative application of electrospray ionisation time-of-flight mass spectrometry (ESI-TOF MS) to oligopeptides recognition using DCC.
A small dynamic library composed of eight functionalised macrocycles has been generated in solution and all members were characterised by ESI-TOF MS. We also probed the dynamic reversibility and mechanism of formation of tetra-carbohydrazide cyclophanes in real-time using ESI-TOF MS.
Dynamic reversibility of tetra-carbohydrazide cyclophanes is favored under thermodynamic control. The mechanism of formation of tetra-carbohydrazide cyclophanes involves key dialdehyde intermediates, which have been detected and assigned according to their high-resolution m/z values. Three members of the dynamic library bind efficiently in the gas phase to a selection of oligopeptides, unique to bacteria, allowing observation of host/guest complex ions in the gas phase.
We probed the mechanism of the [2+2]-cyclocondensation reaction forming library members, proved dynamic reversibility of tetra-carbohydrazide cyclophanes and showed that complex ions formed between library members and hosts can be observed in the gas phase, allowing the solution of an important problem of biological interest. Copyright © 2012 John Wiley & Sons, Ltd.