List of symbols and abbreviations
English | Vietnamese | |
AcOH | Acetic acid | |
br s | broad singlet | Wide single toe |
CC | Chromatography Column | Column chromatography |
CC 50 | The 50% cytotoxic concentration | 50% toxic concentration |
CPT | Camptothecin | |
CTPT | Molecular Formula | |
d | Doublet | Double nose |
DAD | Diode Array Detector | Diode Array Detector |
dd | double of double | Double nose |
DEPT | Detortionless Enhancement by Polarization Transfer | DEPT spectrum |
DMA | Dimethylacetamide | |
DMSO | Dimethyl Sulfoxide | |
DMF | Dimethylformamide | |
DNA | Deoxyribonucleic Acid | |
EG | Ethylene glycol | |
EtOAc | Ethyl acetate | |
EtOH | Ethanol | |
FTIR | Fourier-transform infrared | Infrared spectrum Fourier transform |
h | Hour | Hour |
HPLC | High-Performance Liquid Chromatography | High performance liquid chromatography High |
HMBC | Heteronuclear Multiple Bond Coherence | Heteronuclear interaction spectrum through multiple connections |
HR-ESI-MS | High Resolution Electrospray Ionization Mass Spectrometry | Atomic mass spectrometry high resolution ionization |
HSQC | Heteronuclear Single Quantum Correlation | Heteronuclear interaction spectrum through a joint |
Maybe you are interested!
-
Study on synthesis of TiO2- Fe2O3/GNP materials from ilmenite and graphite ore to orient Cr(VI) transformation in defense industrial wastewater - 8 -
Study on muscle loss in patients with type 2 diabetes and initial evaluation of the effectiveness of exercise intervention - 7 -
Evaluation of Growth Indicator Differences Among Study Cells in Tien Ky Town -
Study on synthesis of TiO2- Fe2O3/GNP materials from ilmenite and graphite ore to orient Cr(VI) transformation in defense industrial wastewater - 6 -
Study on synthesis of TiO2- Fe2O3/GNP materials from ilmenite and graphite ore to orient Cr(VI) transformation in defense industrial wastewater - 2
Identification | Identification | |
IC 50 | Inhibitory Concentration 50% | 50% inhibitory concentration |
J | Coupling constant | Coupling constant |
m | Multiplet | Multi-tip |
MCRs | Multicomponent reactions | Polyreactions part |
MeOH | Methanol | |
MsOH | Methanesulfonic acid | |
MW | Microwave | Microwave oven |
nm | Nanometer | |
NMR | Nuclear Magnetic Resonance | Nuclear magnetic resonance |
RT (rt) | Room Temperature | Room temperature |
RMSD | Root-mean-square deviation | Root-mean-deviation square |
OD | Optical Density | Optical density |
PDB | Protein Data Bank | Data Bank protein |
PL | Appendix | |
ppm | parts per million | Million |
S | Singlet | Single point |
SAR | Structure-Activity Relationship | The relationship between activity properties and structure |
SD | Standard deviation | Standard deviation |
SDS | Sodium dodecyl sulfate | |
STT | Numerical order | |
t | Triplet | Tip three |
TLC | Thin Layer Chromatography | Thin layer chromatography |
TMS | TetramethylSilane | |
TopI-DNA | Topoisomerase I-DNA | |
δ | Chemical shift | Chemical shift |
| Microphone |
List of tables
Table 1.1. Cytotoxic activity of sulfonyl bisbenzimidazole derivatives 9
Table 1.2. Biological activity of benzimidazole derivatives containing pyrazole ring 10
Table 1.3. IC50 values of 4a-4s derivatives 11
Table 1.4. Structures of benzimidazole- 1,3,4-oxadiazole derivatives 13
Table 1.5. Cytotoxic activity of 5a-5o derivatives, doxorubicin and Hoechst 33342 13
Table 2.1. Chemicals used in the synthesis process 35
Table 2.2. Tools and equipment used in synthesis 36
Table 2.3. Structures of synthetic benzimidazole derivatives 37
Table 2.4. Structures of synthetic indole derivatives 42
Table 2.5. Software and equipment used in the docking process 48
Table 3.1. Structure and synthetic yield of synthesized benzimidazole derivatives ..53
Table 3.2. Structure and performance of synthetic indole derivatives 55
Table 3.3. Cytotoxic results of benzimidazole derivatives 125
Table 3.4. Cytotoxic results of indole derivatives 134
Table 3.5. Cytotoxicity results on cancer cells and normal cells of derivatives 53H, 5MM, IPM and BPM 138
Table 3.6. Re-docking results with TopI-DNA complex (PDB ID: 1T8I) 139
Table 3.7. Docking results of three benzimidazole derivatives 5MM, 53H and 3BO and camptothecin on the TopI-DNA complex (PDB ID: 1T8I) 140
Table 3.8. Docking results of the three best indole derivatives and camptothecin on the enzyme 1T8I 143
vii
List of diagrams
Scheme 1.1. Some benzimidazole ring condensation reactions between o-phenylendiamine and mono or dicarboxylic acid 15
Scheme 1.2. Condensation reactions of benzimidazole framework from o-phenylendiamine with aldehydes 16
Scheme 1.3. Some reactions of benzimidazole ring closure from o-phenylendiamine and acid anhydride derivatives 16
Scheme 1.4. Synthesis of benzimidazole derivatives from o-phenylendiamine with ortho-esters
.......................................................................................................................................... 17
Scheme 1.5. Synthesis of 2,5-dimethylbenzimidazole derivative 17
Scheme 1.6. Indole ring-closing reactions using transition metal catalysts 22
Scheme 1.7. Classical indole ring-closing reactions without transition metal catalysts 22
Diagram 1.8. Mechanism of the Mannich reaction 24
Scheme 1.9. Synthesis of 3-aminomethyl indole derivatives 25
Scheme 1.10. Synthesis of indole derivatives by Mannich reaction using L-proline catalyst (top), SDS surfactant and water (bottom) 25
Scheme 1.11. Mannich reaction of indole, benzaldehyde and succinimide in DMF 26 solvent
Scheme 1.12. Mannich reaction in the synthesis of indole derivatives using MsOH and TBAI 26
Scheme 2.1. Synthesis of benzimidazole derivatives 37
Scheme 2.2. Mechanism of benzimidazole ring closure reaction 41
Scheme 2.3. Synthesis of indole derivatives 42
Scheme 2.4. Mannich reaction mechanism for the formation of 3-aminoalkylated indole derivatives 45
Diagram 2.5. Metabolism of MTT salt under the influence of mitochondria 47
List of images
Figure 1.1. Structure of vitamin B12 7
Figure 1.2. Enantioconversion of 5(6)-methylbenzimidazole derivative 7
Figure 1.3. Some anticancer drugs containing the benzimidazole framework 8
Figure 1.4. Some commercial drugs containing the indole 18 framework
Figure 1.5. Incremental construction docking algorithm 28
Figure 1.6. Triangulation of the ligand at the binding site of protein 29
Figure 1.7. Description of the enzymes topoisomerase I (TopI) and topoisomerase II (TopII) unwinding the DNA strand 29
Figure 1.8. Structure of the human TopI-DNA enzyme complex (TopI-DNA) 30
Figure 1.9. (a) Structure of CPT, (b) Three-dimensional structure of the CPT-TopI-DNA ternary complex, (c) CPT inserted into the DNA helix, and (d) amino acids in the active site of CPT in the complex 31
Figure 1.10. Topoisomerase I-DNA complex inhibitors containing the benzimidazole 32 backbone
Figure 1.11. Docking results of 5n: (A) 5n located in the active cavity of the TopI-DNA complex, (B) Key interactions of 5n with the active cavity of the TopI-DNA complex, (C) Structure of 5n 32
Figure 1.12. Inhibitors of the indole backbone-containing Topoisomerase I-DNA complex
.......................................................................................................................................... 33
Figure 1.13. (A) Structure of the evodiamine derivative 29u (B) Docking conformation of 29u and CPT superimposed (C) 29u bound to the active site of TopI-DNA 34
Figure 2.1. Synthesis of benzimidazole derivatives, stage (1) 40
Figure 2.2. Synthesis of benzimidazole derivatives, stage (2) 41
Figure 2.3. Synthesis steps of 3-aminoalkylated indole derivatives 44
Figure 2.4. Binding cavity structure of TopI complex and double-stranded DNA with ligand CPT 50
Figure 3.1. Intramolecular hydrogen bonding of 2-(5(6)-substituted-1H-benzimidazol-2-yl)-phenol derivatives 109
Figure 3.2. Relationship between the structure of synthesized benzimidazole derivatives and their inhibitory activity against cancer cells 133
Figure 3.3. Relationship between the structure of synthetic indole derivatives and their inhibitory activity against cancer cells 138
Figure 3.4. Superposition of the cocrystallized ligand CPT conformations onto the crystal of the TopI-DNA complex (PDB: 1T8I). Double-stranded DNA and TopI are represented by green and blue bands 140
Figure 3.5. 5MM derivative at the CPT binding cavity of the TopI-DNA complex 141
Figure 3.6. 53H derivative at the CPT binding cavity of the TopI-DNA complex 141
Figure 3.7. Camptothecin in the binding cavity of the TopI-DNA complex 142
Figure 3.8. 3D and 2D models of CPT (A and B), 5MM (C and D), and 53H (E and F) inserted into the binding cavity of the TopI-DNA complex 143
Figure 3.9. BPM derivative at the CPT binding cavity of the TopI-DNA complex 144
Figure 3.10. IPM derivative at the CPT binding cavity of the TopI-DNA complex 144
Figure 3.11. PPM derivative at the CPT binding cavity of the TopI-DNA complex 145
Figure 3.12. 3D and 2D models of BPM (A and B), IPM (C and D), and PPM (E and F) inserted into the binding cavity of the TopI-DNA complex 146
INTRODUCTION
According to a report in February 2021, in the past 10 years, the FDA has approved nearly 400 drugs, with cancer drugs leading the way (25%), followed by drugs for the treatment of infectious diseases (15%) and neurological disorders (11%) [1]. According to statistics from the World Health Organization (WHO), every year there are about 10.1 million new cases of cancer worldwide and about 6.7 million people die from cancer, of which the death rate from cancer accounts for 12% of all causes of death in humans [2]. The above figures show that cancer treatment is still a top concern for humanity. However, many patients still have to stop treatment due to side effects of current cancer drugs. 33% of breast cancer patients treated with palbociclib combined with letrozole were forced to stop treatment and 40-45% of patients were forced to reduce the dose due to side effects of the drug such as nausea, hair loss, joint pain, osteoporosis, weakness, fatigue, etc. [3]. Therefore, finding new anti-cancer drugs that are more effective and have fewer side effects is a top concern today.
Heterocyclic compounds always occupy an important position in pharmaceutical synthesis research. Among them, benzimidazole and indole are among the most widely used compounds because they have many biological activities such as anti-cancer [4, 5], anti-helminthic [6], anti-fungal [7], anti-bacterial [8], anti-viral [9], neurotransmitter [10]... In addition, in some anti-cancer drugs currently circulating on the market, there is still the presence of benzimidazole and indole frameworks in the structure such as nocodazole, abemaciclib, selumetinib and bendamustine, vincristine and vinblastine. However, like other cancer drugs, they also have many side effects such as constipation, headache, some blood sugar problems, hair loss [10]... Therefore, the search for new anti-cancer agents based on the framework of benzimidazole and indole with better cancer cell inhibitory activity and fewer side effects is still being continued. On that scientific basis, the topic: " Synthesis and evaluation of cytotoxic activity of benzimidazole and indole derivatives " contributes to the scientific basis for research and search for new anti-cancer agents.
Research objectives of the thesis
1. Synthesis of benzimidazole derivatives based on the condensation reaction of ortho-phenylenediamine and benzaldehyde derivatives; and synthesis of indole derivatives by the Mannich multiplex reaction.
2. Evaluate the anticancer cell activity of the synthesized benzimidazole and indole derivatives; evaluate the anticancer cell activity of the derivatives with the best anticancer cell activity; study the relationship between the activity and structure of the derivatives, in order to find potential derivatives.
3. Propose the mechanism of inhibition of cancer cells of the most active benzimidazole and indole derivatives using molecular docking model.
Main research contents
1. Synthesis of benzimidazole derivatives by condensation ring-closing reaction using Na 2 S 2 O 5 as reagent and synthesis of indole derivatives by Mannich multiplex reaction.
2. Determine the chemical structures of the synthesized benzimidazole and indole derivatives.
3. Evaluation of the inhibitory activity of the synthesized benzimidazole and indole derivatives against A549 (lung cancer), MDA-MB-231 (breast cancer), PC3 (prostate cancer) cells and HEK 293 (human embryonic kidney stem cells) of the derivatives with the best cytotoxic effect on cancer cells. Analysis of the relationship between their activity and structure.
4. Build docking models of benzimidazole and indole derivatives with the best cytotoxic activity on the target enzyme topoisomerase I (PDB ID: 1T8I) to explain their cell inhibition mechanism.
New contributions of the thesis
1. Synthesis of 64 benzimidazole derivatives and 14 indole derivatives, including 16 completely new benzimidazole structures and 5 indole structures, according to SciFinder November 2021.
2. First determination of cytotoxic activity of: (i) 60 benzimidazoles on A549 cell line, 64 benzimidazoles on MDA-MB-231 and PC3 cell lines; (ii) 14 indoles on three cell lines A549, MDA-MB-231 and PC3; (iii) 2 benzimidazoles and 2 indoles on HEK 293 cell line, according to SciFinder November 2021.
3. Explain the mechanism of cancer cell inhibition of the most active benzimidazole and indole derivatives using molecular docking model on topoisomerase I-DNA complex and compare with positive control camptothecin.