الفهرس 
introduction
cause of cancerOnly 14 pages are availabe for public view
 |  | from | 167 |  |  |
| | | from | 167 | | |
Abstract
Abstract
This study includes an overview about cancer and the role played by tyrosine kinase in cancer progression. A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50 values in the low nanomolar range (<0.495-9.05 nM) and displayed more potent cytotoxic effect in BaF/3 cell linesexpressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3 expressing Del19/T790M and Ba/F3 expressing L858R/T790M were assayed. Compounds XII, XIVb, XVb showed significant inhibition (IC50= 1.76-2.38 μM) in these mutant lines and significant HER2 enzyme inhibition (IC50= 19.2-40.6 nM) compared to lapatinib (60.1 nM) as well as cytotoxic effect against BT-474 cells of high HER2 expression. The Binding mode of compounds VIIId, XIVb, IXb, IXc and Xb were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds XIVb and XVb showed about eight and three folds respectively greater potency than gefitinib. Our structure-activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing inhibitors against wild type and mutant EGFR.
The thesis is divided into different parts:
1. Introduction:
This part includes a brief survey about cancer, causes of cancer and several approaches for treatment of cancer in addition to targeted cancer therapy with special focus on epidermal growth factor kinases (EGFR).
2. Rational and design:
It describes the scientific basis upon which the targeted quinazoline based compounds were designed, Compounds were designed to target gefitinib resistant cell lines without cytotoxicity of covalent inhibitors. Design is based on two main strategies; first strategy was
Abstract
xvi
based on targeting of EGFR double mutants L858R/T790M and Del19/T790M by adding additional hydrogen bond acceptor at C6 position of quinazoline. Second strategy was based on dual inhibition of EGFR/HER2 to target compensatory pathway of acquired resistance of EGFR inhibition. In addition, a molecular docking study was performed to support the design of the proposed compounds.
3. Results and discussion:
This part includes the different chemical methods adopted for the synthesis of the intermediates and targeted compounds. Also, a brief spectral data concerning the synthesized compounds are cited. Additionally, the results of the biological evaluation (in vitro anticancer activity against different cell lines (BaF/3 WT, Ba/F3 L858R, Ba/F3 L858R/T790M and Del19/T790M, NSCLC PC9 (Del19) and PC9-GR4 (del19/T790M) and BT-474) and EGFR and Her2 kinase activity enzyme inhibition assay) are discussed. Molecular modeling and docking studies as well as ADMET studies were also discussed.
4. Conclusion:
This part includes a summary of the findings and SAR studies towards synthesis of effective EGFR inhibitors against gefitinib resistant cell lines.
5. Experimental:
This part includes the experimental details for the synthesis of the intermediates and final compounds, in addition to their spectral analysis. Also the methods adopted for performing the biological screening are cited.
The study involved the synthesis of the following unavailable reported intermediates:
1. 3-chloro-4-((3-fluorobenzyl)oxy)aniline (A)
2. 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene (B)
3. (E)-N′-(2-cyano-4-nitrophenyl)-N,N-dimethylimidoformamide (II)
4. 4-(3-Bromophenylamino)-6-nitroquinazoline IIIa
5. 4-(3-Ethynylphenylamino)-6-nitroquinazoline IIIb
Abstract
xvii
6. 4-(4-Chlorophenylamino)-6-nitroquinazoline IIIc
7. 4-(3,4-Dichlorophenylamino)-6-nitroquinazoline IIId
8. 4-(3-Chloro-4-fluorophenylamino)-6-nitroquinazoline IIIe
9. 4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]-6-nitroquinazoline IIIf
10. N4-(3-Bromophenyl)-4,6-quinazolinediamine IVa
11. N4-(3-Ethynylphenyl)quinazoline-4,6-diamine IVb
12. N4-(4-Chlorophenyl)quinazoline-4,6-diamine IVc
13. N4(-3,4-Dichlorophenyl)quinazolin-4,6-diamine IVd
14. N4-(3-chloro-4-fluorophenyl)quinazoline-4,6-diamine IVe
15. N4-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)quinazoline-4,6-diamine IVf
In addition, the study comprised the synthesis and characterization of the following non-reported intermediates
1. Phenyl (4-((3-bromophenyl)amino)quinazolin-6-yl)carbamate (VIIa )
2. Phenyl (4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)carbamate (VIIb)
3. Phenyl (4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl) carbamate (XIII)
Furthermore, it has comprised the synthesis and characterization of the following targeted compounds:
1. 1-(4-((4-bromophenyl)amino)quinazolin-6-yl)urea (Va)
2. 1-(4-((4-ethynylphenyl)amino)quinazolin-6-yl)urea (Vb)
3. 1-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)urea (Vc)
4. 1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)urea (XI)
5. N-(4-((4-bromophenyl)amino)quinazolin-6-yl)acetamide (VIa)
6. N-(4-((4-ethynylphenyl)amino)quinazolin-6-yl)acetamide (VIb)
7. N-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)acetamide (VIc)
Abstract
xviii
8. N-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)acetamide (XII)
9. 1-(4-((4-bromophenyl)amino)quinazolin-6-yl)-3-(2-morpholinoethyl)urea (VIIIa)
10. 1-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-3-(2-morpholinoethyl)urea (VIIIc)
11. 1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)-3-(2-morpholinoethyl)urea (XIVa)
12. 1-(4-((4-bromophenyl)amino)quinazolin-6-yl)-3-(2-(piperidin-1-yl)ethyl)urea (VIIIb)
13. 1-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-3-(2-(piperidin-1-yl)ethyl)urea (VIIId)
14. 1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)-3-(2-(piperidin-1-yl)ethyl)urea (XIVb)
15. 1-(4-((3-bromophenyl)amino)quinazolin-6-yl)-3-(2-(piperidin-1-yl)ethyl)thiourea ( IXa)
16. 1-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-3-(2-(piperidin-1-yl)ethyl)thiourea (IXc)
17. 1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)-3-(2-(piperidin-1-yl)ethyl)thiourea (XVb)
18. 1-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-3-(2-morpholinoethyl) thiourea (IXb)
19. 1-(4-((3,4-dichlorophenyl)amino)quinazolin-6-yl)-3-(2-morpholinoethyl)thiourea (IXd)
20. 1-(4-((4-chlorophenyl)amino)quinazolin-6-yl)-3-(2-morpholinoethyl)thiourea (IXe)
21. 1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)-3-(2-morpholinoethyl)thiourea (XVa)
22. 1-(4-((3-bromophenyl)amino)quinazolin-6-yl)-3-(3-morpholinopropyl)thiourea (Xa)
23. 1-(4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-3-(3-morpholinopropyl)thiourea (Xb)
Abstract
xix
24. 1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)-3-(3-morpholinopropyl)thiourea (XVI)
6. References:
The thesis contains 184 references covering the period till 2016.