Design, Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs
Abstract
:1. Introduction
Rationale of Molecular Design
- A flat hetero aromatic ring system that contains at least one H-bond acceptor. It occupies the phthaloyl binding pocket and can form hydrogen bonding interactions with His359 and hydrophobic stacking interactions with Pro354.
- A hydrophobic moiety interacting with the hydrophobic region of the glutarimide binding pocket forming Van der Waals interactions with Trp382, Trp388, Trp402, and Phe 404.
- A linker occupying the space region between the glutarimide binding pocket and the phthaloyl binding pocket.
- A hydrophilic head (three adjacent hydrogen-bond-forming groups) that occupies the hydrophilic region of the glutarimide binding pocket forming hydrogen bonding interactions with His380 and Trp382.
- The binding of immunomodulatory drugs (IMiDs), e.g., thalidomide, with CRBN has been associated with teratogenicity. CRBN has a mediating role in helping immunomodulatory drugs to exert their immunomodulatory and tumoricidal effects. However, the idea that cereblon modulation is responsible for the teratogenic activity of thalidomide in chicks and zebrafish was brought into doubt due to a 2013 report that pomalidomide does not cause teratogenic effects in the same animal models of thalidomide, even though it binds with CRBN more strongly than thalidomide [41,42].
- With regard to the cytotoxicity of IMiDs, CRBN likely plays an important role in the binding, ubiquitination, and degradation of factors involved in maintaining the regular function of a cell [43].
- The molecular requirement for ‘thalidomide-type’ teratogenicity is highly structure-dependent. Both the phthalimide and glutarimide groups are essential for embryopathic activity. It is also evident that the glutarimide moiety contributes to the teratogenic effect of many thalidomide analogs because they simply have R and S stereoisomers, where S is a potential teratogen [44].
- Different studies revealed that phthalimide analogs devoid of the glutarimide moiety could be involved in teratogenic effect. Other results indicate that phthalimide analogs devoid of this functional group could represent a new class of analgesic and anti-inflammatory candidates with potentially greater safety [45].
2. Results
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. In Vitro Anti-Proliferative Activity
2.2.2. In Vitro Protein Expression Assay
Estimation of Human Vascular Endothelial Growth Factor (VEGF) in HepG-2 Supernatant
Caspase-8 Activity Assay in HepG-2 Cell Lysate
Estimation of Nuclear Factor Kappa-B P65 (NF-κB P65) in HepG-2 Cell Lysate
The Effects on TNF-α Levels in HepG-2 Cells
Annexin V-FITC Apoptosis Assay
Cell Cycle Analysis
2.2.3. Structure–Activity Relationships (SAR)
3. Materials and Methods
3.1. Chemistry and Analysis
3.1.1. General Method for Synthesis of Compound III
3-((2-Chloroquinazolin-4-yl)amino)piperidine-2,6-dione III
3.1.2. General Procedure for Synthesis of Compounds VIIa-d
N′-(2-Chloroquinazolin-4-yl)benzohydrazide VIIa
N′-(2-Chloroquinazolin-4-yl)-2-hydroxybenzohydrazide VIIb
4-Chloro-N′-(2-chloroquinazolin-4-yl)benzohydrazide VIIc
2-Chloro-N′-(2-chloroquinazolin-4-yl)benzohydrazide VIId
3.1.3. 2,2′-(Quinazoline-2,4-diyl) bis(N-ethylhydrazine-1-carbothioamide) XI
3.1.4. 2-(2-Chloroquinazolin-4-yl)-N-phenylhydrazine-1-carboxamide XII
3.1.5. General Procedure for Synthesis of Compounds XIIIa-d
2-(2-Chloroquinazolin-4-yl)-N-propylhydrazine-1-carbothioamide XIIIa
N-Allyl-2-(2-chloroquinazolin-4-yl) hydrazine-1-carbothioamide XIIIb
2-(2-Chloroquinazolin-4-yl)-N-cyclohexylhydrazine-1-carbothioamide XIIIc
2-(2-Chloroquinazolin-4-yl)-N-phenylhydrazine-1-carbothioamide XIIId
3.1.6. General Procedure for Synthesis of Compounds XIVa-c
N′-(2-Chloroquinazolin-4-yl)benzenesulfonohydrazide XIVa
N′-(2-Chloroquinazolin-4-yl)-4-methylbenzenesulfonohydrazide XIVb
N′-(2-Chloroquinazolin-4-yl)-4-fluorobenzenesulfonohydrazide XIVc
3.1.7. Diethyl 1-(2-chloroquinazolin-4-yl)hydrazine-1,2-dicarboxylate XVI
3.1.8. General Procedure for Synthesis of Compound 4-[(2-Chloroquinazolin-4-yl)oxy]benzohydrazide XVIII
4-[(2-Chloroquinazolin-4-yl)oxy]benzohydrazide XVIII
2-(4-((2-Chloroquinazolin-4-yl)oxy)benzoyl)hydrazine-1-carboxamide XIX
4-[(2-Chloroquinazolin-4-yl)oxy]-N-(2,6-dioxopiperidin-3-yl)-benzamide XX
3.2. Biological Evaluation
3.2.1. In Vitro Antiproliferative Activities
3.2.2. In Vitro Protein Expression Assay
3.2.3. Apoptosis Assay
3.2.4. Cell Cycle Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound No. | In Vitro Cytotoxicity IC50 (µg/mL) a,b | ||
---|---|---|---|
HepG-2 | PC3 | MCF-7 | |
III | 9.73 ± 0.66 | 13.52 ± 0.28 | 23.14 ± 0.4 |
VIIa | 16.16 ± 0.67 | 11.23 ± 0.54 | 8.82 ± 0.45 |
VIIb | 12.72 ± 0.635 | 15.45 ± 0.69 | 11.29 ± 0.55 |
VIIc | 20.35 ± 0.73 | 25.47 ± 0.79 | 30.61 ± 0.89 |
VIId | 16.31 ± 0.69 | 19.54 ± 0.72 | 12.78 ± 0.58 |
XI | 13.90 ± 0.87 | 12.24 ± 0.83 | 6.18 ± 0.5 |
XII | 4.57 ± 0.12 | 5.82 ± 0.15 | 3.61 ± 0.1 |
XIIIa | 2.03 ± 0.11 | 2.51 ± 0.2 | 0.82 ± 0.02 |
XIIIb | 7.83 ± 0.46 | 9.36 ± 0.47 | 6.89 ± 0.24 |
XIIIc | 9.72 ± 0.54 | 10.12 ± 0.51 | 7.19 ± 0.43 |
XIIId | 11.24 ± 0.55 | 13.39 ± 0.64 | 10.24 ± 0.53 |
XIVa | 6.76 ± 0.23 | 7.67 ± 0.44 | 4.81 ± 0.13 |
XIVb | 3.41 ± 0.1 | 6.73 ± 0.23 | 2.8 ± 0.06 |
XIVc | 2.14 ± 0.05 | 4.98 ± 0.15 | 5.57 ± 0.16 |
XVI | 21.64 ± 0.75 | 31.01 ± 0.81 | 20.16 ± 0.74 |
XIX | 21.32 ± 0.74 | 36.49 ± 1.25 | 21.98 ± 0.78 |
XX | 16.62 ± 0.7 | 20.23 ± 0.73 | 13.45 ± 0.67 |
Thalidomide | 11.26 ± 0.54 | 14.58 ± 0.57 | 16.87 ± 0.7 |
Comp. No. | Caspase-8 (ng/mL) | VEGF (pg/mL) | NFκB P65 (pg/mL) | TNF-α (pg/mL) |
---|---|---|---|---|
XII | 3.4 ± 0.4 * | 225.1 ± 17.2 ** | 121.3 ± 14.6 ** | 76.4 ±14.6 ** |
XIIIb | 4.05 ±0.5 * | 201.5 ± 19.5 ** | 118.5 ± 18.3 ** | 93.2 ± 12.5 * |
XIVc | 7.9 ± 1.2 ** | 152.6 ± 14.5 ** | 63.1 ± 11.05 ** | 53.4 ± 11.2 ** |
Control | 1.08 ± 0.2 | 432.5 ± 25.5 | 278.1 ± 18.5 | 162.5 ± 15.5 |
Thalidomide | 8.3 ±1.2 ** | 153.2 ± 13.4 ** | 110.5 ± 13.2 ** | 53.1 ±12.5 ** |
Compound | Normal Cell | Early Apoptosis | Late Apoptosis | Total Apoptosis | Necrosis |
---|---|---|---|---|---|
Control | 98.61 ± 5.7 | 1.19 ± 0.7 | 0.18 ± 0.01 | 1.37 ± 0.09 | 0.02 ± 0.0 |
Thalidomide | 95.98 ± 12.3 | 3.76 ± 0.9 | 0.26 ± 0.017 | 4.02 ± 0.1 | 0.00 ± 0.0 |
XIVc | 92.08 ± 11.23 | 7.75 ± 1.2 * | 0.15 ± 0.03 | 7.90 ± 0.1 | 0.02 ± 0.0 |
Compound | G0/G1 | S | G2/M |
---|---|---|---|
Control | 10.05 | 59.55 | 29.73 |
Thalidomide | 8.07 | 66.38 | 25.54 |
XIVc | 10.64 | 65.05 | 24.31 |
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Mabrouk, R.R.; Abdallah, A.E.; Mahdy, H.A.; El-Kalyoubi, S.A.; Kamal, O.J.; Abdelghany, T.M.; Zayed, M.F.; Alshaeri, H.K.; Alasmari, M.M.; El-Zahabi, M.A. Design, Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs. Int. J. Mol. Sci. 2023, 24, 12416. https://doi.org/10.3390/ijms241512416
Mabrouk RR, Abdallah AE, Mahdy HA, El-Kalyoubi SA, Kamal OJ, Abdelghany TM, Zayed MF, Alshaeri HK, Alasmari MM, El-Zahabi MA. Design, Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs. International Journal of Molecular Sciences. 2023; 24(15):12416. https://doi.org/10.3390/ijms241512416
Chicago/Turabian StyleMabrouk, Reda R., Abdallah E. Abdallah, Hazem A. Mahdy, Samar A. El-Kalyoubi, Omar Jamal Kamal, Tamer M. Abdelghany, Mohamed F. Zayed, Heba K. Alshaeri, Moudi M. Alasmari, and Mohamed Ayman El-Zahabi. 2023. "Design, Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs" International Journal of Molecular Sciences 24, no. 15: 12416. https://doi.org/10.3390/ijms241512416