Medicinal Chemistry of Quinazolines as Anticancer Agents Targeting Tyrosine Kinases
Abstract
:1. Introduction
2. Therapeutic Importance of Quinazolines
3. Physicochemical Characters of the Core Structural Feature of Anticancer Quinazolines
4. Methods of Preparation of Quinazolines
- Transition metals-catalyzed method. The nitrobenzamide derivative is reduced by palladium chloride (PdCl2) and iron pentacarbonyl Fe(CO)5 in presence of iodobenzene to give 2-phenyl-4(3H)-quinazolinone. This reaction is performed by a microwave-assisted reaction at 110 °C for 0.5 h with 85% yield (Figure 9) [36].
5. Mode of Action of Quinazolines as Anticancer Agents
5.1. Crystallographic Studies of Quinazolines
5.2. Protein Kinases Inhibitors
- Tyrosine kinases responsible for phosphorylation of phenolic hydroxyl (OH) group.
- Serine-threonine kinases responsible for phosphorylation of serine and threonine amino acids.
- Histidine-kinases responsible for phosphorylation of nitrogen in histidine residues.
- Epidermal growth factor receptor (EGFR);
- Platelet derived growth factor receptor (PDGFR);
- Vascular endothelial growth factor receptor (VEGFR);
- Fibroblast growth factor receptor (FGFR).
5.2.1. Epidermal Growth Factor Receptor (EGFR) Inhibitors
- Tyrosine kinase inhibitors molecules which act as a competitive inhibitor on EGFR;
- Monoclonal antibodies which interfere with the binding of EGF and TGF-α.
6,7-Substituted-4-anilinoquiazolines as Anticancer Agents
6-Substituted-4-anilinoquinazoline Derivatives
Structural activity relationship studies (SAR)
- The 4-anilinoquinazoline with substitution at the C-6 and/or the C-7 positions is the general pharmacophoric group required for the EGFR inhibitory activity. These structural requirements are shown by the common tyrosine-kinase inhibitors such as gefitinib, erlotinib, and other anticancer pharmaceutically marketed products.
- The electron-withdrawing groups such as fluoro, bromo, chloro, and ethylene at the aniline ring is advantageous for the antiproliferative activity.
- The 3-bromo substituted quinazoline molecules displayed potent activity.
- The 3-chloro-4-fluoro-aniline substituted quinazoline molecules showed strong activity.
- Changing the aniline moiety at the 4-position with other groups decreased the activity.
- The electron donating groups at the 6 and/or the 7-positions improved the binding activity of N1 and N3 of quinazoline system with the binding pocket.
- The propoxy linker at the C-6 and/or the C-7 of quinazoline moiety showed stronger activity than the methoxy group.
- Dioxygenated groups at the 6 and the 7 positions of quinazoline moiety improved the cytotoxic activity.
- The Michael addition group at 6-position of quinazoline leads to irreversible binding with the receptor-site.
5.2.2. Vascular Endothelial Growth Factor Receptors (VEGFR) Inhibitors
SAR of VEGFR Inhibitors
- Quinazolin-4-aniloino or quinazoline-4-oxyaryl scaffold is required for VEGFR inhibitory activity.
- Substitution at the 6-position of the quinazoline moiety with an electron-releasing group enhances the activity.
- Substitution at the 7-position of the quinazoline with an aminoalkoxy group increases the activity.
- Aromatic spacer between urea or thiourea and N or O at the 4-position of quinazoline is necessary for the activity.
5.2.3. PDGFR Inhibitors
5.2.4. Serine-Threonine Kinase Inhibitors
- Serine-threonine receptor type kinase (TGFBR).
- Serine-threonine non-receptor type kinas (aurora kinases, CDK, and PI3K).
Aurora Kinase Inhibitors
SAR of Aurora Kinase Inhibitors
- Quinazoline with an aminoalkyl or an aminoaryl moiety at the 4-position of the quinazoline is required for the anticancer activity.
- Substitution at the 5 and the 6-positions of the quinazoline with an electron releasing group increases the activity.
- A lipophilic aromatic group attached to the 4-aminoaryl group increases the activity.
Cyclin-Dependent Kinase (CDK) Inhibitors
Phosphoinositid-3-Kinase (PI3K) Inhibitors
6. Pharmaceutical Marketed Anticancer Quinazolines
7. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Character | 4-Aminoquinazoline |
---|---|
Molecular formula | C8H9N3 |
Molecular weight | 147.18 g/mol |
Number of heavy atoms | 11 |
Number of aromatic heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Number of rotatable bonds | 0 |
Number of H-bond acceptors | 2 |
Number of H-bond donors | 2 |
Molar refractivity | 51.25 |
Tropological polar surface area | 50.41 A2 |
Lipophilicity | 0.66 |
Water solubility | Soluble |
GI absorption | High |
BBB permeation | No |
Bioavailability score | 0.55 |
Lipinski | Yes |
Synthetic accessibility | Easy |
Molecular Structure | Generic Name | Chemical Name | Biological Target |
---|---|---|---|
Gefitinib Iressa Irressat NSC 759856 UNII-S65743JHBS ZD 1839 CCRIS 9011 | 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline | Tyrosine kinase (EGFR) IC50 = 33 nM | |
Erlotinib HSDB 8082 UNII-J4T82NDH7E | 4-Quinazolinamine, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)- | Tyrosine kinase (EGFR) IC50 = 2 nM | |
Vandetanib Caprelsa HSDB 8198 UNII-YO460OQ37K Zactima ZD 6474 | 4-Quninazolinamine, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-4-piperidinyl)methoxy)- | Tyrosine kinase (VEGFR2) IC50 = 40 nM | |
Dacomitinib Vizimpro UNII-5092U85G58 PF-00299804 | 2-Butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-6-quinazolinyl)-4-(1-piperidinyl)-, hydrate (1:1), (2E)- | Tyrosine kinase (EGFR) IC50 = 50 nM | |
Afatinib BIBW 2992 Tomtovok Tovok UNII-41UD74L59M | 2-Butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((3S)-tetrahydro-3-furanyl)oxy)-6-quinazolinyl)-4-(dimethylamino)-, (2E)- | Tyrosine kinase (EGFR) IC50 = 0.5 nM | |
Canertinib UNII-C78W1K5ASF | N-(4-((3-Chloro-4-fluorophenyl)amino)-7-(3-(morpholin-4-yl)propoxy)quinazolin-6-yl)prop-2-enamide | Tyrosine kinase (EGFR) IC50 = 0.8 nM | |
Trimetrexate Trimetrexatum HSDB 6545 JB 11 NSC 249008 TMQ UNII-UPN4ITI8T4 | 2,4-Quinazolinediamine, 5-methyl-6-(((3,4,5-trimethoxyphenyl)amino)methyl) | Dihydrofolate reductase (DHFR) IC50 = 0.04 nM | |
Lapatinib GSK 572016 HSDB 8209 Tykerb UNII-0VUA21238F | 4-Quinazolinamine, N-(3-chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)-2-furanyl) | Tyrosine Kinase (EGFR) IC50 = 10.8 nM; (HER) IC50 = 29.2 nM | |
Raltitrexed D 1694 UNII-FCB9EGG971 ZD1694 | L-Glutamic acid, N-((5-(((1,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methylamino)-2-thienyl)carbonyl) | Thymidylate synthase inhibitor IC50 = 9 nM | |
Cediranib USAN AZD-2171 Recentin UNII-NQU9IPY4K9 | Quinazoline, 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy-7-(3-(1-pyrrolidinyl)propoxy) | Tyrosine Kinase (VEGFR) IC50 = 0.4 nM | |
Tandutinib CT 53518 MLN 518 NSC 759851 NII-E1IO3ICJ9A | 1-Piperazinecarboxamide, 4-(6-methoxy-7-(3-(1-piperidinyl)propoxy)-4-quinazolinyl)-N-(4-(1-methylethoxy)phenyl) | Tyrosine Kinase (PDGFR) IC50 = 0.20 μM | |
Barasertib AZD 1152 UNII-16XC2U7W8N | 1H-Pyrazole-3-acetamide, 5-((7-(3-(ethyl(2- (phosphonooxy)ethyl)amino)propoxy)-4-quinazolinyl)amino)-N-(3-fluorophenyl) | Tyrosine Kinase (Aurora B) IC50 = 0.37 nM | |
Idelalisib GS 1101 UNII-YG57I8T5M0 Zydelig HSDB 8408 CAL-101 | 5-Fluoro-3-phenyl-2-((S)-1-(9H-purin-6-ylamino)-propyl)-3H-quinazolin-4-one | Tyrosine Kinase (PI3Kδ) IC50 = 2.5 nM | |
Copanlisib BAY 80-6946 UNII-WI6V529FZ9 Aliqopa | 2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo(1,2-c)quinazolin-4-yl)pyrimidine-5-carboxamide | Tyrosine Kinase (PI3Kα) (PI3Kϒ) IC50 = 19 nM |
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Zayed, M.F. Medicinal Chemistry of Quinazolines as Anticancer Agents Targeting Tyrosine Kinases. Sci. Pharm. 2023, 91, 18. https://doi.org/10.3390/scipharm91020018
Zayed MF. Medicinal Chemistry of Quinazolines as Anticancer Agents Targeting Tyrosine Kinases. Scientia Pharmaceutica. 2023; 91(2):18. https://doi.org/10.3390/scipharm91020018
Chicago/Turabian StyleZayed, Mohamed F. 2023. "Medicinal Chemistry of Quinazolines as Anticancer Agents Targeting Tyrosine Kinases" Scientia Pharmaceutica 91, no. 2: 18. https://doi.org/10.3390/scipharm91020018