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The Development of Novel Antibiotics Using Chemical Evolution
Hani Fathi Nour
Assistant ResearcherNational Research Centre, Egypt
M.Sc. Cairo University 2007DAAD scholarship holder 2008
Jacobs University Bremen, Germany
Thesis Committee
1. Prof. Dr. Nikolai Kuhnert2. Prof. Dr. Marcelo Fernández-Lahore3. Prof. Dr. Sijbren Otto
Supervisor: Prof. Dr. Nikolai Kuhnert
©
2An 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
3Dynamic versus traditional combinatorial chemistry
Traditional combinatorial chemistry
+
Dynamic combinatorial chemistry (DCC)
+++++++++
4Chemistry of trianglimines
1
5Synthesis of highly functionalised trianglimines
O
Br
FHNu
O
Br
Nu
BOH
HO
O
Nu
O
O
Nu
O
O
H2N NH2
H2N
H2N
NuO O
NH2
NH2
• Nucleophilic aromatic substitution
• Suzuki-coupling reaction
• Condensation
O
O
Nu
C3-Symmetrical Unsymmetrical
6Separation of trianglimine regioisomers
N N
NN
N N
N
OO
N
OO
N
O
O
N N
NN
N N
N
OO
N
OO
N
OO
2
3
7Monitoring the [3+3]-cyclocondensation reaction by ESI/TOF MS
290.2611 747.4909 893.59320.0
Intens.
200 400 600 800 1000 1200
443.2801
637.3991
0.5
1.0
1.5
5x10
m/z
326.1287
443.2808
637.3997
777.5626 893.5943
0.00
0.25
0.50
0.75
1.00
1.25
5x10
Intens.
200 400 600 800 1000 1200 m/z
Intens.
637.4081
0
1
2
3
4
200 400 600 800 1000 1200 m/z
1 h
2 h
3 h
N N
OHCN
H2N
C28H34N4O442
N
N
N N
N
N
636C42H48N6
4
1
8Monitoring the [3+3]-cyclocondensation reaction by ESI/TOF MS
290.2612327.2543 347.1759
425.2714
443.2798
637.4026
0.0
0.5
1.0
1.5
2.0
4x10
Intens.
250 300 350 400 450 500 550 600 650 m/z
N
N
N
N
7N
NN
NH2
O
8
NN
OO
6
N
NH2
N
H2N
5 NN
NN
NN
9
1 h
425.2776
637.4079
0.0
0.5
1.0
1.5
2.0
5x10
Intens.
200 400 600 800 1000 1200 m/z
N
N
N
N
7
NN
NN
NN
9
12 h
9
7
9Conformation of trianglimines
2
10
N N
NN
N N
O
O
O
N N
NN
N N
O
O
O
N N
NN
N N
N
N
N
NN
N
N N
NN
N N
N
OO
N
OO
N
OO
N N
NN
N N
N
OO
N
OO
N
O
O
10 (37%) 2 (31%)
11 (22%) 3 (4%)
12 (11%)
11
N N
NN
N N
N
N
N
N
N
NO
OO
O
OO
N N
NN
N N
N
N
N
N
OO
OO
NNO
O
NH HN
HNNH
NH HN
O
O
O NH HN
HNNH
NH HN
O
O
O
NaBH4 THF/MeOH
N N
NN
N N
NH HN
HNNH
NH HN
13 (35%) 14 (10%)
15 (99%) 16 (99%)
14
13
12
Paper 1 13
Probing the mechanism and dynamic reversibility of trianglimine formation 14
Exact mechanism for formation of trianglimines
17
18 19
20
21 22
1
15
Exact mechanism for formation of trianglimines
How were the pyramids built?
N NH2
O
N NH2
N
NH2
N NH2
N
N O
N NH2
H2NN
N N
N N
NN
N N
Who revealed the stepwise mechanism of trianglimines?
A PhD student in Kuhnert group, Hany Nour
16
Dynamic reversibility of trianglimines
N N
N N
N N
N
N
N
OO
N
NO
O
NO
O
13
N N
N N
N N
O
O
O
15
N
N
OO
O
OO
O
O
H2N
H2N
NH2
NH2
N
NO
O
O O
H2N NH2
N
NO
O
O
O
O
O
O
NH2
NH2
H2N
H2N
H2N NH2
OO O
17
N
N
OO
O
O
OO
O
H2N
H2N
N
NO
O
O O
H2N NH2
N
NO
O
O
O
O
O
O
OO O
NH2
NH2
H2N
H2N
H2N NH2
NH2
NH2
N N
N N
N N
O
O
O
15
N N
N N
N N
N
N
N
OO
N
NO
O
NO
O
13
18
N
NO
O
O
O 24
O
O
O
25
H2N NH2
23
N N
N N
N N
O
O
O
15
N N
N N
N N
O
O N
NO
O
26 New
N N
N N
N N
NO
NO
O
N
NO
O
27 New
1 : 1 : 2
19
Paper 2 20
Trianglimine
Somet
hing e
lse
Nothing is more difficult, and therefore more precious, than to be able to decide (Napoleon Bonaparte)
Jetzt muss ich mich entscheiden!
21
Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles
28 2923
30 31
22
Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles
32
33
34
23
Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles
35 36 (57%)
37 38 (63%)
35 39 (88 %)
37 40 (70 %)
24
47, 4948, 50
4144
4245
4346
44
41-43 44-46
47-48 49-50
25
48
48
26
X-Ray structure by Gawroński et al .
Conformation of Tetra-carbohydrazide cyclophanes
48a
48b
27
Structure of Tetra-carbohydrazide cyclophanes versus structure of trianglimines
51
52
33
53
28
Conformation of non-protected Tetra-carbohydrazide cyclophanes 29
Paper 3 30
54 55 (88%)
56 57 (77%)
58 3558 (55%)
58 3759 (56%)
60 61
62
31
259.1319
539.2550
775.4022
1033.5420
0.0
0.5
1.0
1.5
2.0
5x10
Intens.
500 1000 1500 2000 2500 m/z
517.2706
63
32Self-assembled dioxolane dihydrazides
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
Synthesis of Tetra-carbohydrazide cyclophanes as a novel class of macrocycles
70, X = O (88 %)71, X = NPh (89 %)
65
34
Manuscript 4, submitted to Chem. Eur. J. 35
O O
NHO
HNO NH2H2N
58
O O
NHO
HNO NH2H2N
36
O
O O
72
N
OO
73
O
O
NHO NH2
HNOH2N
A
HNOH2N
NHO NH2
D
O
C
O
72 73
74 75
36
O O
NHO
HNO NH2H2N
58
O O
NHO
HNO NH2H2N
36
O
O O
72
N
OO
73
O
O
NHO NH2
HNOH2N
A
HNOH2N
NHO NH2
D
O
C
O
76 77
78 79
37
72 73
74 75
NHO N
HNO
HNON
NHO N
N
72B B
D
D
NHO N
HNO
HNON
NHO N
N
73C C
D
D
NHO N
HNO
HNON
NHO N
N
74B B
A
A
38
76 77
78 79
NHO N
HNO
HNON
NHO N
N
72B B
D
D
NHO N
HNO
HNON
NHO N
N
73C C
D
D
NHO N
HNO
HNON
NHO N
N
74B B
A
A
39
72
73
74
75
76
77
78
79
72
737475767778
79
OO
NHHNN NH2O O
X
O
OO
NHHNN NO O
X
O
Y
O
O
O
NH
NHN
H2N
O
O
X
NHN
O
O
HNNH2
O
O
R1 R2R2R1
86 R1 = R2 = H, X = Y = O87 R1 = R2 = H, X = Y = NPh88 R1 = R2 = (CH2)5, X = Y = O89 R1 = R2 = H, X = NPh, Y = O90 R1 = R2 = (CH2)5, X = NPh, Y = O
80 R1 = R2 = H, X = O81 R1 = R2 = H, X = NPh82 R1 = R2 = (CH2)5, X = O
80-82 86-90
83 R1 = R2 = H, X = O84 R1 = R2 = H, X = NPh85 R1 = R2 = (CH2)5, X = O
83-85 R1
R2
R1
R2
40
76
72
80 86
47 83
41Mechanism of Tetra-carbohydrazide cyclophanes formation
O O
NHO
HNO NH2H2N
91
N
O O
O O
NHO
HNO NH2H2N
36
O
O O
72
N
OO
73
O
O
NHO NH2
HNOH2N
A
HNOH2N
NHO NH2
D
O
C
O
92 93
94 95
42
O O
NHO
HNO NH2H2N
91
N
O O
O O
NHO
HNO NH2H2N
36
O
O O
72
N
OO
73
O
O
NHO NH2
HNOH2N
A
HNOH2N
NHO NH2
D
O
C
O
96 97
98 99
43
(98)
(95)
(93)
(99)
(97)
(92)
(96) (94)
Frag Frag
NHO N
HNO
HNON
NHO N
N
95B C
D
D
NHO N
HNO
HNON
NHO N
N
93
A
B B
D
NHO N
HNO
HNON
NHO N
N
97
A
B C
D
44ESI-TOF/MS spectrum for a small DCL of Tetra-carbohydrazide cyclophanes
O
NH
O OHN
OHO
O
NH
NH2
OHN
O
NH
OHN
OH
OHN
OHO
O O
NH
NH2
OHN
O
NH
OHN
OH
O
NH
NH2
O OHN
O
NH
OHN
OH
100 AcNH-D-Ala-D-Glu-L-Lys-D-Ala-D-Ala-Gly-COOH 101 AcNH-D-Glu-L-Lys-D-Ala-D-Ala-Gly-COOH
102 AcNH-L-Lys-D-Ala-D-Ala-Gly-COOH
45Oligopeptides which mimic bacterial cell wall structure
Three self-assembled molecules of guest 102
Four self-assembled molecules of guest 102
NHO N
HNO
HNON
NHO N
N
95/102
B C
D
D
NHO N
HNO
HNON
NHO N
N
93/102
A
B B
D
NHO N
HNO
HNON
NHO N
N
97/102
A
B C
D
46
NHO N
HNO
HNON
NHO N
N
97/102
A
B C
D
NHO N
HNO
HNON
NHO N
N
97
A
B C
D
102
47MS/MS spectrum for host/guest complex 97/102
Paper 5, accepted manuscript in RCM
48
Paper 6, tetra-(hydrazinecarboxamide) cyclophanes, a novel class of polyamide macrocycles 49
36 R1 = R2 = H 54 R1 = R2 = CH3
58 R1 + R2 = (CH2)5
105-110
105 R1 = R2 = H, X = O (94%) 106 R1 = R2 = H, X = CH2 (99%)107 R1 = R2 = CH3, X = O (89%)
108 R1 = R2 = CH3, X = CH2 (90%)
109 R1 + R2 = (CH2)5, X = O (97%)110 R1 + R2 = (CH2)5, X = CH2 (99%)
105-110
50Synthesis of tetra-(hydrazinecarboxamide) cyclophanes
103 X = O104 X = CH2
105a syn/anti
105b syn/syn 105c anti/anti
107
51
52Paper 6, manuscript will be submitted to Eur. J. Org. Chem.
Paper 7, bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors 53
111, R1 = R2 = R3 = H, R4 = OCH3 112, R1 + R2 = (CH2)5, R3 = H, R4 = OCH3 113, R1 = R2 = H, R3 = R4 = OCH3 114, R1 = R2 = R3 = H, R4 = N(CH3)2
OO
NHO
HNO NH2H2N
OO
NHO
HNO NH2H2N
OO
NHO
HNO NH2H2N
R R R R S S
36 58 38
OO
NHO
HNO NHHN
R R
ONH
OHN
R2R1
R3
R4 R4
R3
OO
NHO
HNO NHHN
S S
ONH
OHN
R2R1
R3
R4 R4
R3
115, R1 = R2 = R3 = H, R4 = OCH3 116, R1 = R2 = H, R3 = R4 = OCH3 117, R1 = R2 = R3 = H, R4 = N(CH3)2
111
112
113
114
115
116
117
78%
74%
93%
89%
96%
99%
93%
54Bis-N-substituted hydrazinecarboxamides, a novel class of two armed receptors
55Conformation of bis-N-substituted hydrazinecarboxamides
111
56
57
111D-(‒)-quinic acid
58
O
NH
O OHN
OHO
O
NH
NH2
OHN
O
NH
OHN
OH
100 AcNH-D-Ala-D-Glu-L-Lys-D-Ala-D-Ala-Gly-COOH
OO
NHO
HNO NHHN
R R
ONH
OHN
OO
111
OO
NHO
HNO NHHN
R R
ONH
OHN
OO
113
OO
OO
NHO
HNO NHHN
R R
ONH
OHN 114
N N
59
111113100
113114100
111113114100
60Selective recognition of bis-N-substituted hydrazinecarboxamides
61Paper 7, manuscript will be submitted to Tetrahedron
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
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
65Possible applications of the novel tetra-(hydrazinecarboxamide) cyclophanes
NHO N
HNO
HNON
NHO N
NNH
O NHN
O
HNON
NHO N
NM
M
References
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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
4th 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:
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66
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 C3-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
68Acknowledgement
Prof. Dr. Nikolai KuhnertProf. Dr. Marcelo Fernández-LahoreProf. Dr. Sijbren OttoMrs. Anja Müller
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