Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming:
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| Main Author: | |
|---|---|
| Format: | Thesis Book |
| Language: | English |
| Published: |
Heidelberg
[2020]
|
| Subjects: | |
| Online Access: | Inhaltsverzeichnis Inhaltsverzeichnis |
| Physical Description: | 137 Seiten Illustrationen, Diagramme 30 cm |
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MARC
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| 100 | 1 | |a Saleh, Sawsan |d 1980- |e Verfasser |0 (DE-588)1155603400 |4 aut | |
| 245 | 1 | 0 | |a Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming |c presented by M.Sc. Sawsan Saleh |
| 264 | 1 | |a Heidelberg |c [2020] | |
| 300 | |a 137 Seiten |b Illustrationen, Diagramme |c 30 cm | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |b Dissertation |c Ruperto Carola University Heidelberg, Germany |d 2020 | ||
| 650 | 0 | 7 | |a High throughput screening |0 (DE-588)4596131-1 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Stammzelle |0 (DE-588)4665329-6 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Pluripotenz |0 (DE-588)4420540-5 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Kleines Molekül |0 (DE-588)4164124-3 |2 gnd |9 rswk-swf |
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
| 689 | 0 | 0 | |a Stammzelle |0 (DE-588)4665329-6 |D s |
| 689 | 0 | 1 | |a Pluripotenz |0 (DE-588)4420540-5 |D s |
| 689 | 0 | 2 | |a Kleines Molekül |0 (DE-588)4164124-3 |D s |
| 689 | 0 | 3 | |a High throughput screening |0 (DE-588)4596131-1 |D s |
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| adam_text | TABLE
OF
CONTENTS:
TABLE
OF
FIGURES:
.....................................................................................................................................
3
TABLE
OF
FABLES:
......................................................................................................................................
4
LIST
OF
ABBREVIATIONS:
.............................................................................................................................
5
ACKNOWLEDGMENTS:
..............................................................................................................................
7
ZUSAMMENFASSUNG:
...............................................................................................................................
8
SUMMARY:
...............................................................................................................................................
9
INTRODUCTION:
........................................................................................................................................
10
1.
REGENERATIVE
MEDICINE
AND
THE
RISE
OF
STEM
CELL
THERAPY:
...................................................
10
2.
EMBRYONIC
STEM
CELLS:
.................................................................................................................
11
3.
INDUCED
PLURIPOTENT
STEM
CELLS:
............................................................................................
14
4.
INDUCING
PLURIPOTENT
STEM
CELLS
STRATEGIES
AND
TECHNIQUES:
..................................................
15
5.
YAMANAKA
PLURIPOTENCY
FACTORS:
..............................................................................................
18
5.1.
OCT
4
(OCTAMER-BINDING
TRANSCRIPTION
FACTOR
4):
.....................................................................
18
5.2.
SOX2
(SRY
(SEX-DETERMINING
REGION
Y)-BOX
2):
.........................................................................
19
5.3.
C-MYC
(CELLULAR
MYELOCYTOMATOSIS
ONCOGENE):
.....................................................................
19
5.4.
KLF4
(KRUPPEL-LIKE
FACTOR
4):
.......................................................................................................
20
6.
THE
PLURIPOTENCY
MOLECULAR
CIRCUITRY
AND
NANOG,
A
DOWNSTREAM
FACTOR:
...........................
21
6.1.
HOMEOBOX
PROTEIN
NANOG:
.......................................................................................................
21
6.2.
PLURIPOTENCY
MOLECULAR
CIRCUITRY:
...............................................................................................
22
7.
EPIGENETIC
MODIFICATION
IN
REPROGRAMMING:
...........................................................................
23
8.
SMALL
MOLECULES
IN
REPROGRAMMING:
.........................................................................................
24
8.1.
SMALL
MOLECULES
THAT
CAN
IMPROVE
IPSCS
GENERATION
EFFICIENCY:
.........................................
24
8.2.
SMALL
MOLECULES
THAT
CAN
REPLACE
ONE
OR
MORE
YAMANAKA
FACTORS:
...................................
26
8.3.
SMALL
MOLECULES
THAT
CAN
GENERATE
CHEMICAL
MIPSCS
(MURINE
CIPSCS):
............................
26
9.
INTRODUCING
NEW
SMALL
MOLECULES
AND
DRUG-DESIGN:
..............................................................
27
9.1.
HIGH
THROUGHPUT
SCREENING
AND
CELL-BASED
ASSAY:
................................................................
27
9.2.
HIT
TO
LEAD
STEP:
...........................................................................................................................
29
9.3.
LEAD
OPTIMIZATION
STEP:
..............................................................................................................
29
MATERIALS:
.............................................................................................................................................
31
1.1.
CHEMICAL
SYNTHESIS
MATERIALS:
...................................................................................................
31
1.2.
LABORATORY
CONSUMABLE
MATERIALS:
............................................................................................
33
1.3.
EQUIPMENT:
..................................................................................................................................
34
1.4.
BIOLOGICAL
EXPERIMENTS
MATERIALS:
..............................................................................................
35
1.5.
BUFFERS
AND
SOLUTIONS
USED
FOR
THE
BIOLOGICAL
EXPERIMENTS:
....................................................
36
METHODS:
..............................................................................................................................................
37
1.
CHEMICAL
SYNTHESIS
PROTOCOLS
FOR
THE
TESTED
COMPOUNDS:
.....................................................
37
1.1.
CHEMICAL
SYNTHESIS
OF
BENZYLOXYBENZENE
GROUP:
...................................................................
37
1.2.
CHEMICAL
SYNTHESIS
OF
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
-BUTYL):..........................
38
1.3.
CHEMICAL
SYNTHESIS
OF
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL):
...........................
38
1.4.
CHEMICAL
SYNTHESIS
OF
IMIDAZOPYRIDINE
GROUP:
........................................................................
40
1.5.
CHEMICAL
SYNTHESIS
OF
PYRAZOLOPYRIMIDINE
GROUP:
...................................................................
41
2.
STRUCTURE
VERIFICATION
ANALYTICAL
TECHNIQUES:
...........................................................................
42
2.1.
PROTON
NUCLEAR
MAGNETIC
RESONANCE
( H
NMR)
SPECTROSCOPY:
............................................
42
2.2.
CARBON-13
NUCLEAR
MAGNETIC
RESONANCE
(
,3
C
NMR)
SPECTRA
AND
ATTACHED
PROTON
TEST
SPECTRUM
(APT):
...................................................................................................................................
43
2.3.
ELECTROSPRAY
IONIZATION
MASS
SPECTRA
(ESIMS):
.........................................................................
43
2.4.
FOURIER-TRANSFORM
INFRARED
SPECTRUM
(FT/IR):
...........................................................................
43
2.5.
HIGH-PERFORMANCE
LIQUID
CHROMATOGRAPHY
(HPLC):
...............................................................
43
3.
MAMMALIAN
CELL
TISSUE
CULTURE:
.................................................................................................
44
3.1.
SELECTED
MAMMALIAN
CELL
LINES:
................................................................................................
44
3.1.1.
NCCIT:
...................................................................................................................................
44
3.1.2.
HEK293
(HUMAN
EMBRYONIC
KIDNEY
293):
.........................................................................
44
3.1.3.
HFF
(HUMAN
FORESKIN
FIBROBLAST):
.........................................................................................
45
3.2.
MAMMALIAN
CELL
LINES
CONSTRUCTION
(DONE
BY
THE
RESEARCH
GROUP):
...................................
45
1
3.2.1.
HEK293-OCT4
AND
HEK293-SOX2:
.........................................................................................
45
3.2.2.
NCCIT-OCT4
AND
NCCIT-NANOG:
.......................................................................................
45
3.3.
MAMMALIAN
CELL
CULTURE
CONDITIONS:
........................................................................................
46
4.
CYTOTOXICITY
OF
THE
COMPOUNDS
BY
RESAZURIN
REDUCTION
ASSAY:
.............................................
46
4.1.
CELL
CULTURE
PREPARATION
AND
TREATMENT:
.................................................................................
46
4.2.
RESAZURIN
REDUCTION
ASSAY:
........................................................................................................
46
4.3.
STATISTICAL
ASPECTS:
.......................................................................................................................
47
5.
BIOACTIVITY
OF
THE
COMPOUNDS
BY
LUCIFERASE
REPORTER
ASSAY:
...............................................
47
5.1.
CELL
CULTURE
PREPARATION
AND
TREATMENT:
.................................................................................
47
5.2.
LUCIFERASE
REPORTER
ASSAY:
..........................................................................................................
47
5.3.
NORMALIZATION
TO
TOTAL
PROTEIN
CONTENT
USING
BRADFORD
ASSAY:
...............................................
48
5.4.
STATISTICAL
ASPECTS:
.......................................................................................................................
48
6.
PLURIPOTENCY
STAINING
BY
ALKALINE
PHOSPHATASE:
.....................................................................
48
6.1.
CELL
CULTURE
PREPARATION
AND
TREATMENT:
.................................................................................
48
6.2.
ALKALINE
PHOSPHATASE
LIVE-STAINING:
..........................................................................................
49
7.
STATISTICAL
METHODS:
.....................................................................................................................
49
7.1.
R
PACKAGES
AND
GENERATED
SCRIPTS:
.........................................................................................
49
7.1.1.
DPLYR
PACKAGE:
....................................................................................................................
49
7.1.2.
GRMETRICS
PACKAGE:
...........................................................................................................
50
7.1.3.
GGPLOT2
SYSTEM:
....................................................................................................................
50
7.2.
IMAGEJ
AND
ANALYZING
IMAGES:
..............................................................................................
50
RESULTS:
.................................................................................................................................................
51
1.
STRUCTURE
MODIFICATION
AND
CHEMICAL
SYNTHESIS
OF
NEW
SMALL
MOLECULES
CANDIDATES:
......
51
1.1.
BENZYLOXYBENZENE
DERIVATIVES:
..................................................................................................
51
1.2.
ANILINOTHIAZOLE
DERIVATIVES:
........................................................................................................
53
1.2.1.
ANILINOTHIAZOLE
DERIVATIVES
(REPLACEMENT
WITH
TERT
BUTYL)
:
.................................................
53
1.2.2.
ANILINOTHIAZOLE
DERIVATIVES
(REPLACEMENT
WITH
PHENYL):
..................................................
55
1.3.
IMIDAZOPYRIDINE
DERIVATIVES:
.....................................................................................................
56
1.4.
PYRAZOLOPYRIMIDINE
DERIVATIVES:
.................................................................................................
59
2.
STRUCTURE
VERIFICATION
USING
COMBINED
SPECTRA:
......................................................................
61
2.1.
PROTON
NUCLEAR
MAGNETIC
RESONANCE
(1H
NMR)
SPECTRUM:
...................................................
61
2.2.
CARBON-13
NUCLEAR
MAGNETIC
RESONANCE
(
,3
C
NMR)
SPECTRUM:
..........................................
63
2.3.
ATTACHED
PROTON
TEST
SPECTRUM
(APT):
.....................................................................................
65
2.4.
ELECTROSPRAY
IONIZATION
MASS
SPECTRUM
(ESIMS):
......................................................................
66
2.5.
FOURIER-TRANSFORM
INFRARED
SPECTRUM
(FT/IR):
.............................................................................
67
2.6.
HIGH-PERFORMANCE
LIQUID
CHROMATOGRAPH
(HPLC):
.................................................................
68
3.1.
CYTOTOXICITY
AND
IC50
VALUES
FOR
BENZYLOXYBENZENE
GROUP:
...................................................
69
3.2.
CYTOTOXICITY
AND
IC50
VALUES
FOR
ANILINOTHIAZOLE
GROUP:
...........................................................
70
3.2.1.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
-BUTYL)
:
.........................................................
70
3.2.2.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL):
..........................................................
71
3.3.
CYTOTOXICITY
AND
IC50
VALUES
FOR
IMIDAZOPYRIDINE
GROUP:
........................................................
73
3.4.
CYTOTOXICITY
AND
ICSO
VALUES
FOR
PYRAZOLOPYRIMIDINE
GROUP:
...................................................
75
4.
BIOACTIVITY
OF
THE
COMPOUNDS
AND
THEIR
ENHANCEMENT
OF
OCT4:
.........................................
76
4.1.
BENZYLOXYBENZENE
GROUP
ENHANCEMENT
ON
OCT4:
................................................................
76
4.2.
ANILINOTHIAZOLE
GROUP
ENHANCEMENT
ON
OCT4:
.......................................................................
77
4.2.1.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
-BUTYL)
ACTIVITY:
............................................
17
4.2.2.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL)
ACTIVITY:
...........................................
78
4.3.
IMIDAZOPYRIDINE
GROUP
ENHANCEMENT
ON
OCT4:
.....................................................................
78
4.4.
PYRAZOLOPYRIMIDINE
GROUP
ENHANCEMENT
ON
OCT4:
...............................................................
80
5.
BIOACTIVITY
OF
THE
COMPOUNDS
AND
THEIR
ENHANCEMENT
OF
SOX2
AND
NANOG:
....................
80
5.1.
BENZYLOXYBENZENE
GROUP
ENHANCEMENT
ON
SOX2
AND
NANOG:
...........................................
81
5.2.
ANILINOTHIAZOLE
GROUP
ENHANCEMENT
ON
SOX2
AND
NANOG:
...................................................
82
5.2.1.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
~BUTYL)
ACTIVITY:
...........................................
82
5.2.2.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL)
ACTIVITY:
..........................................
83
5.3.
IMIDAZOPYRIDINE
GROUP
ENHANCEMENT
ON
SOX2
AND
NANOG:
................................................
83
5.4.
PYRAZOLOPYRIMIDINE
GROUP
ENHANCEMENT
ON
SOX2
AND
NANOG:
...........................................
85
6.
BIOACTIVITY
OF
THE
COMPOUNDS
ON
REPROGRAMMING
.................................................................
86
2
6.1.
IMIDAZOPYRIDINE
GROUP
PRETREATMENT
ENHANCEMENT
FOR
HFF
REPROGRAMMING:
...................
86
6.2.
BENZYLOXYBENZENE
GROUP
ENHANCEMENT
ON
HFF
REPROGRAMMING:
.......................................
87
6.3.
ANILINOTHIAZOLE
GROUP
ENHANCEMENT
ON
HFF
REPROGRAMMING:
.............................................
89
6.3.1.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
BUTYL)
ACTIVITY:
..........................................
89
6.3.2.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL)
ACTIVITY:
...........................................
90
6.4.
PYRAZOLOPYRIMIDINE
GROUP
ENHANCEMENT
ON
HFF
REPROGRAMMING:
......................................
91
DISCUSSION
AND
CONCLUSIONS:
...............................................................................................................
92
1.
BENZYLOXYBENZENE
DERIVATIVES:
..................................................................................................
92
2.
ANILINOTHIAZOLE
DERIVATIVES:
........................................................................................................
94
2.1.
ANILINOTHIAZOLE
DERIVATIVES
(
,ERT
-BUTYL
REPLACEMENT):
................................................................
94
2.2.
ANILINOTHIAZOLE
DERIVATIVES
(PHENYL
REPLACEMENT):
.................................................................
96
3.
IMIDAZOPYRIDINE
DERIVATIVES:
.....................................................................................................
98
4.
PYRAZOLOPYRIMIDINE
DERIVATIVES:
...............................................................................................
101
CLOSING
REMARKS:
................................................................................................................................
102
REFERENCES:
........................................................................................................................................
104
SUPPLEMENTARY
INFORMATION:
............................................................................................................
113
1.
BENZYLOXYBENZENE
DERIVATIVES:
.................................................................................................
113
2.
ANILINOTHIAZOLE
DERIVATIVES
(
TERT
-BUTYL
REPLACEMENT):
...............................................................
115
3.
ANILINOTHIAZOLE
DERIVATIVES
(PHENYL
REPLACEMENT):
................................................................
117
4.
IMIDAZOPYRIDINE
DERIVATIVES:
....................................................................................................
122
5.
PYRAZOLOPYRIMIDINE
DERIVATIVES:
...............................................................................................
130
R
PROGRAMMING
SCRIPTS:
.....................................................................................................................
134
1.
CONCENTRATION-RESPONSE
CURVES
GENERATING
BY
GGPLOT2:
.....................................................
134
2.
ICSO
VALUES
CALCULATION
USING
GRMETRICS:
................................................................................
135
3.
COMPOUNDS
BIOACTIVITY
ON
PLURIPOTENCY
MARKERS
GENERATED
GRAPHS
USING
GGPLOT2:
......
135
4.
COMPOUNDS
BIOACTIVITY
ON
HFF
REPROGRAMMING
GENERATED
GRAPHS
USING
GGPLOT2:
........
136
TABLE
OF
FIGURES:
FIGURE
1:
HOW
HUMAN
EMBRYONIC
STEM
CELLS
ARE
DERIVED,
TERESE
WINSLOW
2006,
.......................
11
FIGURE
2:
EMBRYONIC
STEM
CELLS
APPLICATIONS,
TERESE
WINSLOW
2006,
1............................................
12
FIGURE
3:
INDUCING
PLURIPOTENT
STEM
CELLS
STRATEGIES
28
....................................................................
16
FIGURE
4:
THE
PLURIPOTENCY
MOLECULAR
CIRCUITRY
100
.............................................................................
23
FIGURE
5:
STRUCTURE
MODIFICATION
OF
BENZYLOXY
BENZENE
DERIVATIVES
..............................................
51
FIGURE
6:
CHEMICAL
SYNTHESIS
OF
BENZYLOXY
BENZENE
DERIVATIVES
....................................................
52
FIGURE
7:
STRUCTURE
MODIFICATION
OF
ANILINOTHIAZOLE
DERIVATIVES
......................................................
53
FIGURE
8:
CHEMICAL
SYNTHESIS
OF
ANILINOTHIAZOLE
DERIVATIVES
(
TER
-FBUTYL
REPLACEMENT)
...................
54
FIGURE
9:
CHEMICAL
SYNTHESIS
OF
ANILINOTHIAZOLE
DERIVATIVES
(PHENYL
REPLACEMENT)
...................
55
FIGURE
10:
STRUCTURE
MODIFICATION
OF
IMIDAZOPYRIDINE
DERIVATIVES
..................................................
57
FIGURE
11:
CHEMICAL
SYNTHESIS
OF
IMIDAZOPYRIDINE
DERIVATIVES
(FIRST
MODIFICATION)
......................
57
FIGURE
12
:
CHEMICAL
SYNTHESIS
OF
IMIDAZOPYRIDINE
DERIVATIVES
(SECOND
MODIFICATION)
...............
59
FIGURE
13:
CHEMICAL
SYNTHSIS
OF
PYRAZOLOPYRIMIDINE
DERIVATIVES
.....................................................
60
FIGURE
14:
PROTON
NUCLEAR
MAGNETIC
RESONANCE
(1H
NMR)
SPECTRUM
FOR
ATPH-M-CI
..................
62
FIGURE
15:
THE
CALCULATED
CHEMICAL
SHIFT
AND
THE
OBSERVED
ONES
FOR
EACH
PROTON
OF
ATPH-M-CI.
..............................................................................................................................................................
63
FIGURE
16:
CARBON-13
NUCLEAR
MAGNETIC
RESONANCE
(13C
NMR)
SPECTRUM
OF
ATPH-M-CI
.........
64
FIGURE
17:
CARBONS
NUMBERS
IN
ATPH-M-CI
.......................................................................................
64
FIGURE
18:
ATTACHED
PROTON
TEST
SPECTRUM
(APT)
FOR
ATPH-M-CI
....................................................
66
FIGURE
19:
ELECTROSPRAY
IONIZATION
MASS
SPECTRUM
(ESIMS)
FOR
ATPH-M-CI
.....................................
67
FIGURE
20
:
FOURIER-TRANSFORM
INFRARED
SPECTRUM
(FT/IR)
FOR
ATPH-M-CI
...........................................
67
FIGURE
21:
HIGH-PERFORMANCE
LIQUID
CHROMATOGRAPH
(HPLC)
FOR
ATPH-M-CI
................................
68
FIGURE
22:
CONCENTRATION-RESPONSE
CURVES
OF
BENZYLOXY
BENZENE
DERIVATIVES
............................
69
FIGURE
23:
CONCENTRATION-RESPONSE
CURVES
OF
ANILINOTHIAZOLE
(REPLACEMENT
WITH
,ERT
-BUTYL)
GROUP.
I
IJJUI
Z_-T
.
^01
111
VX
1
10
1
I
I
V
0
O
1
R
I
11111
I
O
11
11
OTZ-
1
O
1
IKOI
11
VVI
11
1
FOM
LYIJ
..............................................................................................................................................................
72
FIGURE
25:
CONCENTRATION-RESPONSE
CURVES
OF
IMIDAZOPYRIDINE
GROUP
(FIRST
MODIFICATION)
.........
73
3
|
| adam_txt |
TABLE
OF
CONTENTS:
TABLE
OF
FIGURES:
.
3
TABLE
OF
FABLES:
.
4
LIST
OF
ABBREVIATIONS:
.
5
ACKNOWLEDGMENTS:
.
7
ZUSAMMENFASSUNG:
.
8
SUMMARY:
.
9
INTRODUCTION:
.
10
1.
REGENERATIVE
MEDICINE
AND
THE
RISE
OF
STEM
CELL
THERAPY:
.
10
2.
EMBRYONIC
STEM
CELLS:
.
11
3.
INDUCED
PLURIPOTENT
STEM
CELLS:
.
14
4.
INDUCING
PLURIPOTENT
STEM
CELLS
STRATEGIES
AND
TECHNIQUES:
.
15
5.
YAMANAKA
PLURIPOTENCY
FACTORS:
.
18
5.1.
OCT
4
(OCTAMER-BINDING
TRANSCRIPTION
FACTOR
4):
.
18
5.2.
SOX2
(SRY
(SEX-DETERMINING
REGION
Y)-BOX
2):
.
19
5.3.
C-MYC
(CELLULAR
MYELOCYTOMATOSIS
ONCOGENE):
.
19
5.4.
KLF4
(KRUPPEL-LIKE
FACTOR
4):
.
20
6.
THE
PLURIPOTENCY
MOLECULAR
CIRCUITRY
AND
NANOG,
A
DOWNSTREAM
FACTOR:
.
21
6.1.
HOMEOBOX
PROTEIN
NANOG:
.
21
6.2.
PLURIPOTENCY
MOLECULAR
CIRCUITRY:
.
22
7.
EPIGENETIC
MODIFICATION
IN
REPROGRAMMING:
.
23
8.
SMALL
MOLECULES
IN
REPROGRAMMING:
.
24
8.1.
SMALL
MOLECULES
THAT
CAN
IMPROVE
IPSCS
GENERATION
EFFICIENCY:
.
24
8.2.
SMALL
MOLECULES
THAT
CAN
REPLACE
ONE
OR
MORE
YAMANAKA
FACTORS:
.
26
8.3.
SMALL
MOLECULES
THAT
CAN
GENERATE
CHEMICAL
MIPSCS
(MURINE
CIPSCS):
.
26
9.
INTRODUCING
NEW
SMALL
MOLECULES
AND
DRUG-DESIGN:
.
27
9.1.
HIGH
THROUGHPUT
SCREENING
AND
CELL-BASED
ASSAY:
.
27
9.2.
HIT
TO
LEAD
STEP:
.
29
9.3.
LEAD
OPTIMIZATION
STEP:
.
29
MATERIALS:
.
31
1.1.
CHEMICAL
SYNTHESIS
MATERIALS:
.
31
1.2.
LABORATORY
CONSUMABLE
MATERIALS:
.
33
1.3.
EQUIPMENT:
.
34
1.4.
BIOLOGICAL
EXPERIMENTS
MATERIALS:
.
35
1.5.
BUFFERS
AND
SOLUTIONS
USED
FOR
THE
BIOLOGICAL
EXPERIMENTS:
.
36
METHODS:
.
37
1.
CHEMICAL
SYNTHESIS
PROTOCOLS
FOR
THE
TESTED
COMPOUNDS:
.
37
1.1.
CHEMICAL
SYNTHESIS
OF
BENZYLOXYBENZENE
GROUP:
.
37
1.2.
CHEMICAL
SYNTHESIS
OF
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
-BUTYL):.
38
1.3.
CHEMICAL
SYNTHESIS
OF
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL):
.
38
1.4.
CHEMICAL
SYNTHESIS
OF
IMIDAZOPYRIDINE
GROUP:
.
40
1.5.
CHEMICAL
SYNTHESIS
OF
PYRAZOLOPYRIMIDINE
GROUP:
.
41
2.
STRUCTURE
VERIFICATION
ANALYTICAL
TECHNIQUES:
.
42
2.1.
PROTON
NUCLEAR
MAGNETIC
RESONANCE
('H
NMR)
SPECTROSCOPY:
.
42
2.2.
CARBON-13
NUCLEAR
MAGNETIC
RESONANCE
(
,3
C
NMR)
SPECTRA
AND
ATTACHED
PROTON
TEST
SPECTRUM
(APT):
.
43
2.3.
ELECTROSPRAY
IONIZATION
MASS
SPECTRA
(ESIMS):
.
43
2.4.
FOURIER-TRANSFORM
INFRARED
SPECTRUM
(FT/IR):
.
43
2.5.
HIGH-PERFORMANCE
LIQUID
CHROMATOGRAPHY
(HPLC):
.
43
3.
MAMMALIAN
CELL
TISSUE
CULTURE:
.
44
3.1.
SELECTED
MAMMALIAN
CELL
LINES:
.
44
3.1.1.
NCCIT:
.
44
3.1.2.
HEK293
(HUMAN
EMBRYONIC
KIDNEY
293):
.
44
3.1.3.
HFF
(HUMAN
FORESKIN
FIBROBLAST):
.
45
3.2.
MAMMALIAN
CELL
LINES
CONSTRUCTION
(DONE
BY
THE
RESEARCH
GROUP):
.
45
1
3.2.1.
HEK293-OCT4
AND
HEK293-SOX2:
.
45
3.2.2.
NCCIT-OCT4
AND
NCCIT-NANOG:
.
45
3.3.
MAMMALIAN
CELL
CULTURE
CONDITIONS:
.
46
4.
CYTOTOXICITY
OF
THE
COMPOUNDS
BY
RESAZURIN
REDUCTION
ASSAY:
.
46
4.1.
CELL
CULTURE
PREPARATION
AND
TREATMENT:
.
46
4.2.
RESAZURIN
REDUCTION
ASSAY:
.
46
4.3.
STATISTICAL
ASPECTS:
.
47
5.
BIOACTIVITY
OF
THE
COMPOUNDS
BY
LUCIFERASE
REPORTER
ASSAY:
.
47
5.1.
CELL
CULTURE
PREPARATION
AND
TREATMENT:
.
47
5.2.
LUCIFERASE
REPORTER
ASSAY:
.
47
5.3.
NORMALIZATION
TO
TOTAL
PROTEIN
CONTENT
USING
BRADFORD
ASSAY:
.
48
5.4.
STATISTICAL
ASPECTS:
.
48
6.
PLURIPOTENCY
STAINING
BY
ALKALINE
PHOSPHATASE:
.
48
6.1.
CELL
CULTURE
PREPARATION
AND
TREATMENT:
.
48
6.2.
ALKALINE
PHOSPHATASE
LIVE-STAINING:
.
49
7.
STATISTICAL
METHODS:
.
49
7.1.
R
PACKAGES
AND
GENERATED
SCRIPTS:
.
49
7.1.1.
DPLYR
PACKAGE:
.
49
7.1.2.
GRMETRICS
PACKAGE:
.
50
7.1.3.
GGPLOT2
SYSTEM:
.
50
7.2.
IMAGEJ
AND
ANALYZING
IMAGES:
.
50
RESULTS:
.
51
1.
STRUCTURE
MODIFICATION
AND
CHEMICAL
SYNTHESIS
OF
NEW
SMALL
MOLECULES
CANDIDATES:
.
51
1.1.
BENZYLOXYBENZENE
DERIVATIVES:
.
51
1.2.
ANILINOTHIAZOLE
DERIVATIVES:
.
53
1.2.1.
ANILINOTHIAZOLE
DERIVATIVES
(REPLACEMENT
WITH
TERT
BUTYL)
:
.
53
1.2.2.
ANILINOTHIAZOLE
DERIVATIVES
(REPLACEMENT
WITH
PHENYL):
.
55
1.3.
IMIDAZOPYRIDINE
DERIVATIVES:
.
56
1.4.
PYRAZOLOPYRIMIDINE
DERIVATIVES:
.
59
2.
STRUCTURE
VERIFICATION
USING
COMBINED
SPECTRA:
.
61
2.1.
PROTON
NUCLEAR
MAGNETIC
RESONANCE
(1H
NMR)
SPECTRUM:
.
61
2.2.
CARBON-13
NUCLEAR
MAGNETIC
RESONANCE
(
,3
C
NMR)
SPECTRUM:
.
63
2.3.
ATTACHED
PROTON
TEST
SPECTRUM
(APT):
.
65
2.4.
ELECTROSPRAY
IONIZATION
MASS
SPECTRUM
(ESIMS):
.
66
2.5.
FOURIER-TRANSFORM
INFRARED
SPECTRUM
(FT/IR):
.
67
2.6.
HIGH-PERFORMANCE
LIQUID
CHROMATOGRAPH
(HPLC):
.
68
3.1.
CYTOTOXICITY
AND
IC50
VALUES
FOR
BENZYLOXYBENZENE
GROUP:
.
69
3.2.
CYTOTOXICITY
AND
IC50
VALUES
FOR
ANILINOTHIAZOLE
GROUP:
.
70
3.2.1.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
-BUTYL)
:
.
70
3.2.2.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL):
.
71
3.3.
CYTOTOXICITY
AND
IC50
VALUES
FOR
IMIDAZOPYRIDINE
GROUP:
.
73
3.4.
CYTOTOXICITY
AND
ICSO
VALUES
FOR
PYRAZOLOPYRIMIDINE
GROUP:
.
75
4.
BIOACTIVITY
OF
THE
COMPOUNDS
AND
THEIR
ENHANCEMENT
OF
OCT4:
.
76
4.1.
BENZYLOXYBENZENE
GROUP
ENHANCEMENT
ON
OCT4:
.
76
4.2.
ANILINOTHIAZOLE
GROUP
ENHANCEMENT
ON
OCT4:
.
77
4.2.1.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
-BUTYL)
ACTIVITY:
.
17
4.2.2.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL)
ACTIVITY:
.
78
4.3.
IMIDAZOPYRIDINE
GROUP
ENHANCEMENT
ON
OCT4:
.
78
4.4.
PYRAZOLOPYRIMIDINE
GROUP
ENHANCEMENT
ON
OCT4:
.
80
5.
BIOACTIVITY
OF
THE
COMPOUNDS
AND
THEIR
ENHANCEMENT
OF
SOX2
AND
NANOG:
.
80
5.1.
BENZYLOXYBENZENE
GROUP
ENHANCEMENT
ON
SOX2
AND
NANOG:
.
81
5.2.
ANILINOTHIAZOLE
GROUP
ENHANCEMENT
ON
SOX2
AND
NANOG:
.
82
5.2.1.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
~BUTYL)
ACTIVITY:
.
82
5.2.2.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL)
ACTIVITY:
.
83
5.3.
IMIDAZOPYRIDINE
GROUP
ENHANCEMENT
ON
SOX2
AND
NANOG:
.
83
5.4.
PYRAZOLOPYRIMIDINE
GROUP
ENHANCEMENT
ON
SOX2
AND
NANOG:
.
85
6.
BIOACTIVITY
OF
THE
COMPOUNDS
ON
REPROGRAMMING
.
86
2
6.1.
IMIDAZOPYRIDINE
GROUP
PRETREATMENT
ENHANCEMENT
FOR
HFF
REPROGRAMMING:
.
86
6.2.
BENZYLOXYBENZENE
GROUP
ENHANCEMENT
ON
HFF
REPROGRAMMING:
.
87
6.3.
ANILINOTHIAZOLE
GROUP
ENHANCEMENT
ON
HFF
REPROGRAMMING:
.
89
6.3.1.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
TERT
BUTYL)
ACTIVITY:
.
89
6.3.2.
ANILINOTHIAZOLE
GROUP
(REPLACEMENT
WITH
PHENYL)
ACTIVITY:
.
90
6.4.
PYRAZOLOPYRIMIDINE
GROUP
ENHANCEMENT
ON
HFF
REPROGRAMMING:
.
91
DISCUSSION
AND
CONCLUSIONS:
.
92
1.
BENZYLOXYBENZENE
DERIVATIVES:
.
92
2.
ANILINOTHIAZOLE
DERIVATIVES:
.
94
2.1.
ANILINOTHIAZOLE
DERIVATIVES
(
,ERT
-BUTYL
REPLACEMENT):
.
94
2.2.
ANILINOTHIAZOLE
DERIVATIVES
(PHENYL
REPLACEMENT):
.
96
3.
IMIDAZOPYRIDINE
DERIVATIVES:
.
98
4.
PYRAZOLOPYRIMIDINE
DERIVATIVES:
.
101
CLOSING
REMARKS:
.
102
REFERENCES:
.
104
SUPPLEMENTARY
INFORMATION:
.
113
1.
BENZYLOXYBENZENE
DERIVATIVES:
.
113
2.
ANILINOTHIAZOLE
DERIVATIVES
(
TERT
-BUTYL
REPLACEMENT):
.
115
3.
ANILINOTHIAZOLE
DERIVATIVES
(PHENYL
REPLACEMENT):
.
117
4.
IMIDAZOPYRIDINE
DERIVATIVES:
.
122
5.
PYRAZOLOPYRIMIDINE
DERIVATIVES:
.
130
R
PROGRAMMING
SCRIPTS:
.
134
1.
CONCENTRATION-RESPONSE
CURVES
GENERATING
BY
GGPLOT2:
.
134
2.
ICSO
VALUES
CALCULATION
USING
GRMETRICS:
.
135
3.
COMPOUNDS
BIOACTIVITY
ON
PLURIPOTENCY
MARKERS
GENERATED
GRAPHS
USING
GGPLOT2:
.
135
4.
COMPOUNDS
BIOACTIVITY
ON
HFF
REPROGRAMMING
GENERATED
GRAPHS
USING
GGPLOT2:
.
136
TABLE
OF
FIGURES:
FIGURE
1:
HOW
HUMAN
EMBRYONIC
STEM
CELLS
ARE
DERIVED,
TERESE
WINSLOW
2006,
'
.
11
FIGURE
2:
EMBRYONIC
STEM
CELLS
APPLICATIONS,
TERESE
WINSLOW
2006,
1.
12
FIGURE
3:
INDUCING
PLURIPOTENT
STEM
CELLS
STRATEGIES
28
.
16
FIGURE
4:
THE
PLURIPOTENCY
MOLECULAR
CIRCUITRY
100
.
23
FIGURE
5:
STRUCTURE
MODIFICATION
OF
BENZYLOXY
BENZENE
DERIVATIVES
.
51
FIGURE
6:
CHEMICAL
SYNTHESIS
OF
BENZYLOXY
BENZENE
DERIVATIVES
.
52
FIGURE
7:
STRUCTURE
MODIFICATION
OF
ANILINOTHIAZOLE
DERIVATIVES
.
53
FIGURE
8:
CHEMICAL
SYNTHESIS
OF
ANILINOTHIAZOLE
DERIVATIVES
(
TER
-FBUTYL
REPLACEMENT)
.
54
FIGURE
9:
CHEMICAL
SYNTHESIS
OF
ANILINOTHIAZOLE
DERIVATIVES
(PHENYL
REPLACEMENT)
.
55
FIGURE
10:
STRUCTURE
MODIFICATION
OF
IMIDAZOPYRIDINE
DERIVATIVES
.
57
FIGURE
11:
CHEMICAL
SYNTHESIS
OF
IMIDAZOPYRIDINE
DERIVATIVES
(FIRST
MODIFICATION)
.
57
FIGURE
12
:
CHEMICAL
SYNTHESIS
OF
IMIDAZOPYRIDINE
DERIVATIVES
(SECOND
MODIFICATION)
.
59
FIGURE
13:
CHEMICAL
SYNTHSIS
OF
PYRAZOLOPYRIMIDINE
DERIVATIVES
.
60
FIGURE
14:
PROTON
NUCLEAR
MAGNETIC
RESONANCE
(1H
NMR)
SPECTRUM
FOR
ATPH-M-CI
.
62
FIGURE
15:
THE
CALCULATED
CHEMICAL
SHIFT
AND
THE
OBSERVED
ONES
FOR
EACH
PROTON
OF
ATPH-M-CI.
.
63
FIGURE
16:
CARBON-13
NUCLEAR
MAGNETIC
RESONANCE
(13C
NMR)
SPECTRUM
OF
ATPH-M-CI
.
64
FIGURE
17:
CARBONS
NUMBERS
IN
ATPH-M-CI
.
64
FIGURE
18:
ATTACHED
PROTON
TEST
SPECTRUM
(APT)
FOR
ATPH-M-CI
.
66
FIGURE
19:
ELECTROSPRAY
IONIZATION
MASS
SPECTRUM
(ESIMS)
FOR
ATPH-M-CI
.
67
FIGURE
20
:
FOURIER-TRANSFORM
INFRARED
SPECTRUM
(FT/IR)
FOR
ATPH-M-CI
.
67
FIGURE
21:
HIGH-PERFORMANCE
LIQUID
CHROMATOGRAPH
(HPLC)
FOR
ATPH-M-CI
.
68
FIGURE
22:
CONCENTRATION-RESPONSE
CURVES
OF
BENZYLOXY
BENZENE
DERIVATIVES
.
69
FIGURE
23:
CONCENTRATION-RESPONSE
CURVES
OF
ANILINOTHIAZOLE
(REPLACEMENT
WITH
,ERT
-BUTYL)
GROUP.
I
IJJUI
Z_-T
.
^01
111
VX
1
10
1
I
I
V
0
'O'
1
R
\I
11111
I
'
O
'
11
11
'OTZ-
1
\O
1
IKOI
11
VVI
11
1
FOM
LYIJ
.
72
FIGURE
25:
CONCENTRATION-RESPONSE
CURVES
OF
IMIDAZOPYRIDINE
GROUP
(FIRST
MODIFICATION)
.
73
3 |
| any_adam_object | 1 |
| any_adam_object_boolean | 1 |
| author | Saleh, Sawsan 1980- |
| author_GND | (DE-588)1155603400 |
| author_facet | Saleh, Sawsan 1980- |
| author_role | aut |
| author_sort | Saleh, Sawsan 1980- |
| author_variant | s s ss |
| building | Verbundindex |
| bvnumber | BV047451231 |
| ctrlnum | (OCoLC)1242025631 (DE-599)DNB1227960735 |
| discipline | Medizin |
| discipline_str_mv | Medizin |
| format | Thesis Book |
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| genre | (DE-588)4113937-9 Hochschulschrift gnd-content |
| genre_facet | Hochschulschrift |
| id | DE-604.BV047451231 |
| illustrated | Illustrated |
| index_date | 2024-07-03T18:03:20Z |
| indexdate | 2024-07-10T09:12:31Z |
| institution | BVB |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-032853223 |
| oclc_num | 1242025631 |
| open_access_boolean | |
| owner | DE-355 DE-BY-UBR |
| owner_facet | DE-355 DE-BY-UBR |
| physical | 137 Seiten Illustrationen, Diagramme 30 cm |
| publishDate | 2020 |
| publishDateSearch | 2020 |
| publishDateSort | 2020 |
| record_format | marc |
| spelling | Saleh, Sawsan 1980- Verfasser (DE-588)1155603400 aut Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming presented by M.Sc. Sawsan Saleh Heidelberg [2020] 137 Seiten Illustrationen, Diagramme 30 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Ruperto Carola University Heidelberg, Germany 2020 High throughput screening (DE-588)4596131-1 gnd rswk-swf Stammzelle (DE-588)4665329-6 gnd rswk-swf Pluripotenz (DE-588)4420540-5 gnd rswk-swf Kleines Molekül (DE-588)4164124-3 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Stammzelle (DE-588)4665329-6 s Pluripotenz (DE-588)4420540-5 s Kleines Molekül (DE-588)4164124-3 s High throughput screening (DE-588)4596131-1 s DE-604 B:DE-101 application/pdf https://d-nb.info/1227960735/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=032853223&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis 1\p aepgnd 0,29681 20210312 DE-101 https://d-nb.info/provenance/plan#aepgnd 2\p aepgnd 0,05432 20210312 DE-101 https://d-nb.info/provenance/plan#aepgnd 3\p aepgnd 0,05432 20210312 DE-101 https://d-nb.info/provenance/plan#aepgnd |
| spellingShingle | Saleh, Sawsan 1980- Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming High throughput screening (DE-588)4596131-1 gnd Stammzelle (DE-588)4665329-6 gnd Pluripotenz (DE-588)4420540-5 gnd Kleines Molekül (DE-588)4164124-3 gnd |
| subject_GND | (DE-588)4596131-1 (DE-588)4665329-6 (DE-588)4420540-5 (DE-588)4164124-3 (DE-588)4113937-9 |
| title | Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming |
| title_auth | Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming |
| title_exact_search | Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming |
| title_exact_search_txtP | Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming |
| title_full | Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming presented by M.Sc. Sawsan Saleh |
| title_fullStr | Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming presented by M.Sc. Sawsan Saleh |
| title_full_unstemmed | Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming presented by M.Sc. Sawsan Saleh |
| title_short | Characterization of new small molecule drug candidates for their properties in modulating cell reprogramming |
| title_sort | characterization of new small molecule drug candidates for their properties in modulating cell reprogramming |
| topic | High throughput screening (DE-588)4596131-1 gnd Stammzelle (DE-588)4665329-6 gnd Pluripotenz (DE-588)4420540-5 gnd Kleines Molekül (DE-588)4164124-3 gnd |
| topic_facet | High throughput screening Stammzelle Pluripotenz Kleines Molekül Hochschulschrift |
| url | https://d-nb.info/1227960735/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=032853223&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT salehsawsan characterizationofnewsmallmoleculedrugcandidatesfortheirpropertiesinmodulatingcellreprogramming |
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