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The Development of Novel Antibiotics Using Chemical Evolution Hani Fathi Nour Assistant Researcher National Research Centre, Egypt M.Sc. Cairo University.

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Presentation on theme: "The Development of Novel Antibiotics Using Chemical Evolution Hani Fathi Nour Assistant Researcher National Research Centre, Egypt M.Sc. Cairo University."— Presentation transcript:

1 The Development of Novel Antibiotics Using Chemical Evolution Hani Fathi Nour Assistant Researcher National Research Centre, Egypt M.Sc. Cairo University 2007 DAAD scholarship holder 2008 Jacobs University Bremen, Germany Thesis Committee 1. Prof. Dr. Nikolai Kuhnert 2. Prof. Dr. Marcelo Fernández-Lahore 3. Prof. Dr. Sijbren Otto Supervisor: Prof. Dr. Nikolai Kuhnert ©

2 2 An overview and objectives  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion

3 3 Dynamic versus traditional combinatorial chemistry Traditional combinatorial chemistry Dynamic combinatorial chemistry (DCC)

4 4 Chemistry of trianglimines 1

5 5 Synthesis of highly functionalised trianglimines Nucleophilic aromatic substitution Suzuki-coupling reaction Condensation C 3 -SymmetricalUnsymmetrical

6 6 Separation of trianglimine regioisomers 2 3

7 7 Monitoring the [3+3]-cyclocondensation reaction by ESI/TOF MS 290.2611 747.4909893.5932 0.0 Intens. 20040060080010001200 443.2801 637.3991 0.5 1.0 1.5 5 x10 m/z 326.1287 443.2808 637.3997 777.5626 893.5943 0.00 0.25 0.50 0.75 1.00 1.25 5 x10 Intens. 20040060080010001200m/z 4 x10 Intens. 637.4081 0 1 2 3 4 20040060080010001200m/z 1 h 2 h 3 h 4 1

8 8 Monitoring the [3+3]-cyclocondensation reaction by ESI/TOF MS 290.2612 327.2543347.1759 425.2714 443.2798 637.4026 0.0 0.5 1.0 1.5 2.0 4 x10 Intens. 250300350400450 500550 600650 m/z 1 h 425.2776 637.4079 0.0 0.5 1.0 1.5 2.0 5 x10 Intens. 20040060080010001200 m/z 12 h 9 7

9 9 Conformation of trianglimines 2

10 10 10 (37%)2 (31%) 11 (22%)3 (4%) 12 (11%)

11 11 13 (35%)14 (10%) 15 (99%) 16 (99%)

12 14 13 12

13 Paper 1 13

14 Probing the mechanism and dynamic reversibility of trianglimine formation 14

15 Exact mechanism for formation of trianglimines 17 1819 20 21 22 1 15

16 Exact mechanism for formation of trianglimines How were the pyramids built? Who revealed the stepwise mechanism of trianglimines? A PhD student in Kuhnert group, Hany Nour 16

17 Dynamic reversibility of trianglimines 17

18 18

19 1 : 1 : 2 19

20 Paper 2 20

21 Trianglimine Something else Nothing is more difficult, and therefore more precious, than to be able to decide (Napoleon Bonaparte) Jetzt muss ich mich entscheiden! 21

22 Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles 282923 30 31 22

23 Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles 32 33 34 23

24 Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles 3536 (57%) 3738 (63%) 3539 (88 %) 3740 (70 %) 24

25 47, 49 48, 50 41 44 42 45 43 46 44 41-4344-46 47-4849-50 25

26 48 26

27 X-Ray structure by Gawroński et al. Conformation of Tetra-carbohydrazide cyclophanes 48a 48b 27

28 Structure of Tetra-carbohydrazide cyclophanes versus structure of trianglimines 51 52 33 53 28

29 Conformation of non-protected Tetra-carbohydrazide cyclophanes 29

30 Paper 3 30

31 5455 (88%) 5657 (77%) 5835 58 (55%) 5837 59 (56%) 60 61 62 31

32 259.1319 539.2550 775.4022 1033.5420 0.0 0.5 1.0 1.5 2.0 5 x10 Intens. 500 1000 150020002500m/z 517.2706 63 32 Self-assembled dioxolane dihydrazides

33 Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles 64, X = O (97 %) 65, X = NPh (99 %) 66, X = O (94 %) 67, X = NPh (99 %) 68, X = O (98 %) 69, X = NPh (99 %) 33

34 Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles 70, X = O (88 %) 71, X = NPh (89 %) 65 34

35 Manuscript 4, submitted to Chem. Eur. J. 35

36 7273 74 75 36

37 76 77 78 79 37

38 7273 74 75 38

39 76 77 78 79 39

40 72 73 74 75 76 77 78 79 72 73 74 75 76 77 78 79 40

41 76 72 80 86 47 83 41 Mechanism of Tetra-carbohydrazide cyclophanes formation

42 92 93 94 95 42

43 96 97 98 99 43

44 (98) (95) (93) (99) (97) (92) (96) (94) Frag 44 ESI-TOF/MS spectrum for a small DCL of Tetra-carbohydrazide cyclophanes

45 45 Oligopeptides which mimic bacterial cell wall structure

46 Three self-assembled molecules of guest 102 Four self-assembled molecules of guest 102 46

47 47 MS/MS spectrum for host/guest complex 97/102

48 Paper 5, accepted manuscript in RCM 48

49 Paper 6, tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles 49

50 50 Synthesis of tetra-(hydrazinecarboxamide) cyclophanes

51 105a syn/anti 105b syn/syn105c anti/anti 107 51

52 52 Paper 6, manuscript will be submitted to Eur. J. Org. Chem.

53 Paper 7, bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors 53

54 54 Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors

55 55 Conformation of bis-N-substituted hydrazinecarboxamides

56 111 56

57 57

58 111 D-( ‒ )-quinic acid 58

59 59

60 111 113 100 113 114 100 111 113 114 100 60 Selective recognition of bis-N-substituted hydrazinecarboxamides

61 61 Paper 7, manuscript will be submitted to Tetrahedron

62  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion  What are antibiotics?  How do antibiotics attack bacteria?  How do bacteria resist antibiotics?  Aim of thesis  Dynamic versus traditional combinatorial chemistry  Generation of a dynamic combinatorial library ( DCL ) from trianglimine macrocycles  Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles  Generation of a DCL from Tetra-carbohydrazide cyclophanes  ESI-TOF/MS recognition of Tetra-carbohydrazide cyclophanes to oligopeptides  Tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles  Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors  Conclusion 62

63  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert.  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert.  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert.  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert.  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert.  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert.  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert.  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert.  Highly functionalised trianglimine regioisomers were successfully synthesized and purified.  Mechanism of trianglimine formation was investigated and dynamic reversibility was confirmed.  A novel class of chiral tetra-carbohydrazide cyclophanes was synthesized.  Tetra-carbohydrazide cyclophanes showed dynamic exchange with generation of a small DCL.  Three members in the DCL showed recognition to oligopeptides as confirmed by ESI-TOF/MS.  A novel class of polyamide tetra-(hydrazinecarboxamide) cyclophanes was synthesized.  A novel class of two armed bis-N-substituted hydrazinecarboxamide receptors was synthesized.  The novel bis-N-substituted hydrazinecarboxamide receptors showed unique self-assembly.  Most importantly, this work is just a start for an endless collaboration with Prof. Kuhnert. Conclusion 63

64 64

65 65 Possible applications of the novel tetra-(hydrazinecarboxamide) cyclophanes

66 References  J. Gawroński, H. Kołbon, M. Kwit, A. Katrusiak, J. Org. Chem., 2000, 65, 5768.  N. Kuhnert, A. López-Periago, G. Rossignolo, Org. Biomol. Chem., 2005, 3, 524.  N. Kuhnert, A. López-Periago, G. Rossignolo, Org. Biomol. Chem., 2003, 1, 1157.  N. Kuhnert, N. Burzlaff, C. Patel and A. López-Periago, Org. Biomol. Chem., 2005, 3, 1911.  N. Kuhnert, A. López-Periago, G. Rossignolo, Org. Biomol. Chem., 2005, 3, 524.  N. Kuhnert, D. Marsh, D. Nicolau, Tetrahedron: Asymm., 2007, 18, 1648.  N. Kuhnert, B. Tang, Tetrahedron Lett., 2006, 47, 2985.  S. Nielsen, M. Larsen, T. Boesen, K. Schønning, H. Kromann, J. Med. Chem., 2005, 48, 2667.  J. Stewart, J. Comput. Chem., 1989, 10, 221.  H. Nour, M. Matei, B. Bassil, U. Kortz, N. Kuhnert, Org. Biomol. Chem., 2011, 9, 3258.  A. Dahlgren, J. Brånalt, I. Kvarnström, I. Nilsson, D. Musilc, B. Samuelsson, Bioorg. Med. Chem., 2002, 10, 1567.  H. Nour, A. López-Periago, N. Kuhnert, Rapid Comm. Mass Spectrom., 2012, 26, 1070.  H. Nour, N. Hourani, N. Kuhnert, Org. Biomol. Chem., 2012, 10, 4381.  H. Nour, A. Golon, A. Le-Gresley, N. Kuhnert, Chem. Eur. J., 2012, submitted manuscript.  H. Nour, T. Islam, M. Fernández-Lahore, N. Kuhnert, Rapid Comm. Mass Spectrom., 2012, accepted manuscript.  Molecular modeling was carried out using HyperChem software (Release 8.0). Hypercube, Inc., 1115 NW 4 th Street, Gaineville, F1 32601 USA. Trial, version from http://www.hypercube.com  P. Skowronek, M. Kuncewicz, M. Brzostowska, A. Janiak, U. Rychlewska, J. Gawroński, Tetrahedron: Asymm., 2012, 23, 300.  S. Zimmerman, C. VanZyl, J. Am. Chem. Soc., 1987, 109, 7894. 66

67  M. Hegab, A.-S. Abdel-fattah, N. Yousef, H. Nour, A. Mostafa, M. Ellithey, Synthesis, X-ray structure, and pharmacological activity of some 6,6-disubstituted chromeno[4,3-b]- and chromeno[3,4-c]-quinolines, Arch. Pharm. Chem. Life Sci., 2007, 340, 396.  M. Hegab, N. Yousef, H. Nour, M. Ellithey, Synthesis and pharmacological activities of some condensed 4- chloro-2,2-dialkyl chromen-3-carboxaldehyde derivatives, Acta. Pharm., 2008, 58, 15.  H. Nour, M. Matei, B. Bassil, U. Kortz, N. Kuhnert, Synthesis of tri-substituted biaryl based trianglimines: formation of C 3 -symmetrical and non-symmetrical regioisomers, Org. Biomol. Chem., 2011, 9, 3258.  H. Nour, A. López-Periago, N. Kuhnert, Probing the mechanism and dynamic reversibility of trianglimine formation using real-time electrospray ionization time-of-flight mass spectrometry, Rapid Commun. Mass Spectrom., 2012, 26, 1070.  H. Nour, N. Hourani, N. Kuhnert, Synthesis of novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles, Org. Biomol. Chem., 2012, 10, 4381.  H. Nour, A. Golon, A. Le-Gresley, N. Kuhnert, Novel synthesis of enantiomerically pure dioxaspiro[4.5]decane tetra-carbohydrazide cyclophane macrocycles, Chem. Eur. J., 2012, submitted manuscript.  H. Nour, T. Islam, M. Fernández-Lahore, N. Kuhnert, 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., 2012, accepted manuscript.  H. Nour, A. Golon, N. Kuhnert, Synthesis of novel chiral tetra-(hydrazinecarboxamide) cyclophane macrocycles, Eur. J. Org. Chem., 2012, manuscript.  H. Nour, A. Golon, T. Islam, M. Fernández-Lahore, N. Kuhnert, Synthesis, self-assembly and ESI-MS complexation studies of novel chiral bis-N-substituted-hydrazinecarboxamide receptors, manuscript.  N. Kuhnert, F. Dairpoosh, R. Jaiswal, M. Matei, S. Deshpande, A. Golon, H. Nour, H. Karaköse, N. Hourani, Hill coefficients of dietary polyphenolic enzyme inhibitiors: can beneficial health effects of dietary polyphenols be explained by allosteric enzyme denaturing?, J. Chem. Biol., 2011, 4, 109. Publications 67

68 68 Acknowledgement Prof. Dr. Nikolai Kuhnert Prof. Dr. Marcelo Fernández-Lahore Prof. Dr. Sijbren OttoMrs. Anja Müller

69 Fragen? Fragen kostet nichts – aber Antworten ist teuer


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