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

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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 1,2 , Tuhidul Islam 1 , Marcelo Fernández-Lahore 1 and Nikolai Kuhnert 1 * 1 School of Engineering and Science, Centre for Nano and Functional Materials (NanoFun), Jacobs University, 28759 Bremen, Germany 2 National Research Centre, Department of Photochemistry, El Behoose Street, P.O. Box 12622, Dokki, Cairo, Egypt RATIONALE: Over the past few decades, bacterial resistance against antibiotics has emerged as a real threat to human health. Accordingly, there is an urgent demand to develop innovative strategies for discovering new antibiotics. We present the first application 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. METHODS: A small dynamic library composed of 8 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 realtime using ESI-TOF MS. RESULTS: 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. CONCLUSIONS: 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 guests can be observed in the gas phase, allowing the solution of an important problem of biological interest. *Correspondence to: N. Kuhnert, School of Engineering and Science, Jacobs University, P.O. Box 750 561, D-28725 Bremen, Germany, Fax: +49 421 200 3229, Tel: +49 421 200 3120. E-mail: n.kuhnert@jacobs-university.de 1 | P a g e
INTRODUCTION No single class of drugs has improved public health and the quality of life more dramatically than antibiotics. Before the introduction of sulfonamides in the 1930s, β-lactam antibiotics in the 1940s and tetracyclins, aminoglycosides and macrolides in the 1950s, one in three deaths worldwide was attributed to a bacterial infection. [1] Antibiotics clearly represent medicinal chemistry’s ultimate benefit to mankind. Although the success of antibiotics has lead to a temporary victory over bacterial infection there should be little reason for complacency. Many bacterial strains have accomplished a fight back through the development of resistance against many antibiotics only introduced less than 50 years ago. Both mutations and more importantly the efficient and rapid exchange of genetic information between bacteria have resulted in multidrug resistant strains that spread through hospitals at an alarming rate. Currently antibiotic management with stringent policies of “reserve antibiotics” have prevented a humanitarian disaster, but it is clearly evident that there is an urgent need for novel antibiotics, ideally comprising completely different chemical structures and possibly new mechanisms of action as compared to the classical compounds. The development of novel antibiotics should be viewed as a race against time due to the adaptability of bacterial strains. A statement of the World Health Organisation (WHO) predicts that by 2020, 30 % of all bacterial infections cannot be successfully treated because of resistance. [2] While the major pharmaceutical companies have committed themselves to the development of novel antibiotics their strategy relies on traditional medicinal chemistry involving the screening of large numbers of compounds either of natural or synthetic origin and depends on serendipity and the quality and structural diversity of the compound libraries available. A new and radical approach towards the development of novel antibiotics is highly desirable. This approach should take the adaptability of bacteria into account and should be rapid and flexible and therefore able to react in a short period of time towards the threat posed by drug resistance. The principle of evolutionary chemistry, using dynamic combinatorial libraries (DCLs) would be such an option, proposed and developed by Sanders and Lehn. [3-10] It relies on the basic principle that a number of building blocks bind via non-covalent interactions to a given guest molecule. Reversible bond formation between the individual building blocks assembles a stable receptor (macrocyclic or open chained) around the chosen target. The Le-Chatelier principle will drive the 2 | P a g e
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The Development of Novel Antibiotic
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Declaration of Authorship I, Hany N
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Abstract Over the past few decades,
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Chapter 2 Trianglimine Chemistry
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Figure 2.4 Trianglimines 10-12 with
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Abbreviations ACN AcOH Ala Acetonit
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RMS ROESY SjGST TFA THF TLC TMS TOC
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Introduction complete remodel of th
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Introduction following protonation.
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Introduction Lehn and co-workers re
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Introduction Figure 1.8 Generation
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Introduction Figure 1.11 Synthetic
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Introduction Figure 1.13 Generation
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Introduction 1.3.11 Boronic ester e
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Introduction References 1. E. Mouli
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Introduction 51. B. Shi, M. F. Grea
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Introduction Figure 2.2 shows compu
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Introduction incorporate β-cyclode
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Introduction Trianglamine-Zn(R) 2 c
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Introduction 24. J. Gajewy, J. Gawr
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Scope of Work Scope of Work In this
Page 43 and 44: Scope of Work can be obtained from
Page 45 and 46: Scope of Work Figure 3.4 Structures
Page 47 and 48: Scope of Work References 1. G. Wrig
Page 49 and 50: Organic & Biomolecular Chemistry Ci
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Page 53 and 54: View Online Downloaded by Jacobs Un
Page 63 and 64: Paper 2 Rapid Commun. Mass Spectrom
Page 65 and 66: Trianglimine formation mechanism by
Page 75 and 76: Paper 3 Org. Biomol. Chem., 2012, 1
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Page 85 and 86: Paper 4 Chem. Eur. J., 2012, submit
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Page 97 and 98: EXPERIMENTAL All the solvents and r
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Page 101 and 102: Scheme 1. Graphical representation
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Page 105 and 106: In contrast, formation of library m
Page 107 and 108: Figure 5. Generated dynamic library
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Page 113 and 114: [2] WHO World health report 2003. h
Page 115 and 116: [32] B. Lienard, N. Selevsek, N. Ol
Page 117 and 118: FULL PAPER Synthesis and ESI-MS Com
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Page 121 and 122: aimed at assessing molecular recogn
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Page 125 and 126: 2 Similar to the case of trianglimi
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Page 131 and 132: 8 27. Nour, H. F.; Hourani, N.; Kuh
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Page 135 and 136: Supplementary Information: Suppleme
Page 137 and 138: Supplementary Material (ESI) for Or
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Supplementary Material (ESI) for Or
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Monitoring the [3+3]-cyclocondensat
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Monitoring the cyclocondensation re
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Product ions appeared as [M+H] + Fi
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Scheme 1. Assigned higher oligomers
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Supplementary Information: Synthesi
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Scheme 4. Proposed fragmentation me
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DMSO Figure 1. 1 H-NMR spectrum for
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Figure 6. 13 C-NMR spectrum for (4S
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Intens. 7 x10 1.5 200.7 1.0 0.5 0.0
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Intens. 7 x10 200.7 1.5 1.0 0.5 0.0
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Intens. 4 x10 577.2 2.0 1.5 1.0 451
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HN N O O R R NH O O N N HN R O O O
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Intens. 5 x10 727.2 2.0 1.5 1.0 O O
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Intens. 5 x10 697.1 1.5 1.0 728.2 0
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O O O O HN N O O NH N HN N O O NH N
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Figure 38. 1 H-NMR spectrum for mac
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Intens. 5000 276.8 4000 3000 2000 1
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Intens. 7 x10 599.1 1.5 1.0 0.5 0.0
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(a) HN N O O NH O O N (b) HN N O NH
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Scheme 11. Proposed fragmentation m
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Scheme 14. Proposed fragmentation m
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Intens. 4 x10 550.9 3 2 1 0 500 100
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Figure 68. 2D-ROESY spectrum for ma
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Supplementary Information: Novel sy
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Intens. 6 x10 0.8 0.6 0.4 240.9 459
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Figure 9. 1 H-NMR spectrum for macr
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Intens. 5 x10 1.5 968.1 1.0 0.5 813
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Intens. 5 x10 897.4 4 2 335.3 707.3
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Scheme 3. Suggested fragmentation m
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Molecular modelling data for the co
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Figure 1. 1 H NMR spectrum for dica
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Intens. 2000 1493.6091 Host-Guest 1
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Intens. [%] 100 775.3 80 388.1 60 4
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Intens. 600 N HN O O 467.1916 400 O
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Intens. 6000 5000 HN N O O O O NH N
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Table 1. High resolution ESI-TOF da
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i Figure 1. 1 H NMR spectrum for ma
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i Figure 5. 1 H NMR spectrum for ma
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i j Figure 9. 1 H NMR spectrum for
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i Figure 13. DEPT-135 spectrum for
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Scheme 1. General mechanism of frag
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Intens. [%] 100 80 60 40 20 0 O H N
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Intens. [%] 100 1131.3 80 60 40 20
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Intens. 1500 1528.6088 1000 500 150
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Intens. [%] 100 80 60 40 Free guest
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Intens. 4 x10 1085.3575 1.25 1.00 0
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Intens. [%] 100 80 Free guest 586.1
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Synthesis, self-assembly and ESI-MS
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O O HN NH HN O O NH HN O 11 O NH O
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O O HN NH HN O O NH HN O 9 O NH O O
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H 2 O DMSO DMSO Figure 6. 1 H-NMR a
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Intens. 5 x10 5 -MS 487.1588 4 3 2
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Intens. -MS 6 x10 0.8 0.6 0.4 0.2 1
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Intens. -MS 6 x10 O O 350.9 1.5 1.0
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Intens. [%] 100 -MS 486.9 Exact str
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Intens. [%] -MS 100 486.9 80 60 975
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Intens. [%] +MS 100 80 517.2 Exact
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Intens. [%] 100 80 60 +MS 388.1 775
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Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 80 +MS 1031.4939 7
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Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 -MS 2 586.1 80 60 4
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Intens. [%] 100 -MS 2 875.2 Exact s
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Table 1. High resolution ESI-TOF/MS
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4. H. Nour, A. López-Periago, N. K
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