New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Drugs
2.1.1. General Information
2.1.2. Synthesis of 2-Phenyl-4H-benzo[d][1,3] Oxazin-4-one (1)
2.1.3. Synthesis of 3-(4-Acetylphenyl)-2-phenylquinazolin-4(3H)-one (2)
2.1.4. Synthesis of Amino Acid Schiff Bases
2-(1-(4-(4-oxo-2-Phenylquinazolin-3(4H)-yl) phenyl) ethylideneamino) Acetic Acid (3)
2-(1-(4-(4-oxo-2-Phenylquinazolin-3(4H)-yl) phenyl) ethylideneamino) Propionic Acid (4)
2-(1-(4-(4-oxo-2-Phenylquinazolin-3(4H)-yl) phenyl) ethylidene amino)-3-phenyl Propionic Acid (5)
3-Hydroxy-2-(1-(4-(4-oxo-2-phenylquinazolin-3(4H)-yl) phenyl) ethylidene amino) Propionic Acid (6)
3-(4-Hydroxyphenyl)-2-(1-(4-(4-oxo-2-phenylquinazolin-3(4H)-yl) phenyl) ethylidene amino) Propionic Acid (7)
4-Methyl-2-(1-(4-(4-oxo-2-phenylquinazolin-3(4H)-yl) phenyl) ethylideneamino) Pentanoic Acid (8)
6-Amino-2-(1-(4-(4-oxo-2-phenylquinazolin-3(4H)-yl) phenyl) ethylideneamino) Hexanoic Acid (9)
4-Amino-4-oxo-2-(1-(4-(4-oxo-2-phenylquinazolin-3(4H)-yl) phenyl) ethylidene amino) Butanoic Acid (10)
2-(1-(4-(4-oxo-2-Phenylquinazolin-3(4H)-yl) phenyl) ethylideneamino)-2-phenyl Acetic Acid (11)
2-((1H-Indol-3-yl) methyleneamino) Acetic Acid (12)
2-((1H-Indol-3-yl)methyleneamino) Propionic Acid (13)
2-((1H-Indol-3-yl) methyleneamino)-3-phenylpropionic Acid (14)
2-((1H-Indol-3-yl) methyleneamino)-3-hydroxy Propionic Acid (15)
2-((1H-Indol-3-yl) methyleneamino)-3-(4-hydroxyphenyl) Propionic Acid (16)
2-((1H-Indol-3-yl) methyleneamino)-4-methylpentanoic Acid (17)
2-((1H-Indol-3-yl) methyleneamino)-6-aminohexanoic Acid (18)
2-((1H-Indol-3-yl)methyleneamino)-4-amino-4-oxobutanoic Acid (19)
2-((1H-indol-3-yl)methyleneamino)-2-phenylacetic Acid (20)
2.2. In Silico Study
2.3. In Vitro Anticancer Studies on Predicted Compounds
2.3.1. Cell Culture, Maintenance, and Treatment
2.3.2. Cell Cytotoxicity Assay by MTT
2.3.3. Cell Cycle Analysis
2.3.4. QPCR Analysis
2.3.5. Detection of Hexokinase Activity Level (ELISA)
2.3.6. Estimation of Oxidative/Antioxidant Biomarkers
2.3.7. Immunoblotting Analysis
2.3.8. Statistical Analysis
3. Results and Discussion
3.1. Chemistry of the Synthesized Compounds
3.2. In Silico Docking Study
3.3. In Vitro Studies
3.3.1. Cytotoxic Effect of Compounds 11, 20, and Tamoxifen (TAM)
3.3.2. Detection of Cell Cycle Arrest Phase
3.3.3. Altered mRNA Expression of Apoptosis Markers
3.3.4. Inhibition of Warburg Effect through Hexokinase (ELISA)
3.3.5. Oxidative and Antioxidant Biomarkers
3.3.6. Immunoblotting Confirms the AMPK/mTOR Pathway
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Gene | Forward Primer (/5---/3) | Reverse Primer (/5---/3) |
---|---|---|
Bax | GGCTGGACACTGGACTTCCT | GGTGAGGACTCCAGCCACAA |
P53 | TAACAGTTCCTGCATGGGCGGC | AGGACAGGCACAAACACGCACC |
Bcl-2 | TTCGCAGAGATGTCCAGTCA | TTCAGAGACAGCCAGGAGAA |
GAPDH | TGTGTCCGTCGTGGATCTGA | CCTGCTTCACCACCTTCTTGA |
HK | NADH | |||||
---|---|---|---|---|---|---|
(ΔGbind) | Docked Complex (Amino Acid–Ligand) Interactions | Distance (Å) | (ΔGbind) | Docked Complex (Amino Acid–Ligand) Interactions | Distance (Å) | |
3 | −7.7 | −9.4 | H-bonds | |||
Lys202:NZ―compound 3 | 2.98 | |||||
π-π interactions | ||||||
H-bonds | Phe205―compound 3 | 4.28 | ||||
Glu220:OE1―compound 3 | 2.38 | Phe205―compound 3 | 4.29 | |||
π-σ interactions | Phe78―compound 3 | 3.93 | ||||
Pro105:CD―compound 3 | 3.61 | Phe78―compound 3 | 4.23 | |||
π-cation interactions | ||||||
Lys75:NZ―compound 3 | 5.42 | |||||
Lys75:NZ―compound 3 | 5.25 | |||||
4 | −7.6 | −9.5 | H-bonds | |||
Lys202:NZ―compound 4 | 3 | |||||
π-π interactions | ||||||
H-bonds | Phe205―compound 4 | 4.17 | ||||
Ile114:N―compound 4 | 3 | Phe205―compound 4 | 4.18 | |||
π-σ interactions | Phe78―compound 4 | 4.07 | ||||
Met300:CA―compound 4 | 3.87 | Phe78―compound 4 | 4.32 | |||
π-cation interactions | ||||||
Lys75:NZ―compound 4 | 5.71 | |||||
Lys75:NZ―compound 4 | 5.36 | |||||
5 | −8.6 | 3.88 | −10.7 | H-bonds | ||
Glu184:OE2―compound 5 | 2.11 | |||||
π-π interactions | ||||||
Phe205―compound 5 | 4.28 | |||||
π-σ interactions | Phe205―compound 5 | 3.95 | ||||
Met300:CA―compound 5 | Phe78―compound 5 | 4.37 | ||||
Phe78―compound 5 | 4.21 | |||||
π-cation interactions | ||||||
Lys75:NZ―compound 5 | 5.38 | |||||
Lys75:NZ―compound 5 | 5.43 | |||||
Lys75:NZ―compound 5 | 5.91 | |||||
6 | −7.9 | −9.3 | H-bonds | |||
Lys202:NZ―compound 6 | 2.99 | |||||
Glu185:OE2―compound 6 | 2.46 | |||||
H-bonds | π-π interactions | |||||
Tyr90:N--compound 6 | 2.95 | Phe205―compound 6 | 4.12 | |||
π-σ interactions | Phe205―compound 6 | 4.24 | ||||
Met300:CA--compound 6 | 3.91 | Phe78―compound 6 | 4.08 | |||
Phe78―compound 6 | 4.28 | |||||
π-cation interactions | ||||||
Lys75:NZ―compound 6 | 5.55 | |||||
Lys75:NZ―compound 6 | 5.4 | |||||
7 | −8.3 | −11.0 | H-bonds | |||
Asn92:ND2―compound 7 | 2.95 | |||||
H-bonds | Lys202:NZ―compound 7 | 2.87 | ||||
Thr88:OG1―compound 7 | 2.95 | π-π interactions | ||||
Ile114:N―compound 7 | 2.96 | Phe205―compound 7 | 4.1 | |||
Ile114:O―compound 7 | 2.94 | Phe205―compound 7 | 4.18 | |||
Thr232:OG1―compound 7 | 2.65 | Phe78―compound 7 | 4.46 | |||
Phe78―compound 7 | 3.99 | |||||
π-cation interactions | ||||||
Lys75:NZ―compound 7 | 5.88 | |||||
8 | −7.7 | −12.8 | H-bonds | 2.93 | ||
Glu97:OE1―compound 8 | 2.89 | |||||
Tyr180:OH―compound 8 | ||||||
π-σ interactions | π-π interactions | |||||
Pro105:CD―compound 8 | Phe205―compound 8 | 4.14 | ||||
Phe205―compound 8 | 4.24 | |||||
Phe78―compound 8 | 4.35 | |||||
Phe78―compound 8 | 4.05 | |||||
9 | −7.2 | −9.5 | H-bonds | |||
H-bonds | Lys75:NZ―compound 9 | 2.92 | ||||
Lys62:NZ―compound 9 | Gly183:O―compound 9 | 2.35 | ||||
Glu266:OE1―compound 9 | π-π interactions | |||||
Lys267:NZ―compound 9 | Phe205―compound 9 | 4.43 | ||||
π-cation interactions | Phe205―compound 9 | 4.29 | ||||
Lys62:NZ―compound 9 | Phe78―compound 9 | 4.31 | ||||
Phe78―compound 9 | 3.79 | |||||
10 | −8.6 | 3.83 | −9.6 | H-bonds | ||
Glu184:OE2―compound 10 | 2.23 | |||||
Lys202:NZ―compound 10 | 2.88 | |||||
π-π interactions | ||||||
π-σ interactions | Phe205―compound 10 | 4.37 | ||||
Met300:CA―compound 10 | Phe205―compound 10 | 3.94 | ||||
Phe78―compound 10 | 4.41 | |||||
Phe78―compound 10 | 4.15 | |||||
π-cation interactions | ||||||
Lys75:NZ―compound 10 | 5.38 | |||||
Lys75:NZ―compound 10 | 5.3 | |||||
11 | −8.8 | H-bonds | −13.0 | H-bonds | ||
Leu349:N―compound 11 | 2.91 | Lys202:NZ―compound 11 | 2.98 | |||
Tyr373:N―compound 11 | 2.98 | π-π interactions | ||||
Glu376―compound 11 | 2.16 | Phe205―compound 11 | 4.33 | |||
π-cation interactions | Phe205―compound 11 | 3.93 | ||||
Arg369:NH1―compound 11 | 4.45 | Phe78―compound 11 | 4.4 | |||
Arg369:NH1―compound 11 | 3.78 | Phe78―compound 11 | 4.19 | |||
Arg369:NH2―compound 11 | 5.98 | π-cation interactions | ||||
Arg369:NH2―compound 11 | 4.98 | Lys75:NZ―compound 11 | 5.21 | |||
Lys75:NZ―compound 11 | 5.33 | |||||
12 | H-bonds | −7.1 | H-bonds | |||
Thr232:N―compound 12 | 3.1 | Asn92:ND2―compound 12 | 2.96 | |||
Thr232:N―compound 12 | 2.93 | Asn92:ND2―compound 12 | 3.01 | |||
Gly233:N―compound 12 | 2.83 | Tyr180:O―compound 12 | 1.86 | |||
π-cation interactions | π-π interactions | |||||
Lys418:NZ―compound 12 | 5.93 | Tyr180―compound 12 | 4.72 | |||
Lys418:NZ―compound 12 | 5.98 | Tyr180―compound 12 | 3.98 | |||
13 | −8.0 | H-bonds | ||||
Asn92:ND2―compound 13 | 2.95 | |||||
H-bonds | Asn92:ND2―compound 13 | 2.98 | ||||
Gly303:N―compound 13 | Tyr180:O―compound 13 | 1.81 | ||||
Thr336:OG1―compound 13 | π-π interactions | |||||
Tyr180―compound 13 | 4.74 | |||||
Tyr180―compound 13 | 4.04 | |||||
14 | H-bonds | −8.4 | ||||
Thr88:N―compound 14 | 2.95 | |||||
Thr88:OG1―compound 14 | 2.92 | |||||
Thr232:N―compound 14 | 2.85 | H-bonds | ||||
Thr232:N―compound 14 | 2.85 | Tyr180:O―compound 14 | 2.94 | |||
Thr232:OG1―compound 14 | 2.99 | π-π interactions | ||||
Gly233:N―compound 14 | 2.94 | Tyr180―compound 14 | 4.75 | |||
π-cation interactions | ||||||
Lys418:NZ―compound 14 | 4.02 | |||||
Lys418:NZ―compound 14 | 4.43 | |||||
15 | H-bonds | −7.8 | H-bonds | |||
Thr88:N―compound 15 | 2.9 | Asn92:ND2―compound 15 | 2.93 | |||
Thr88:OG1―compound 15 | 2.87 | Ser96:N―compound 15 | 2.93 | |||
Thr232:N―compound 15 | 2.98 | Ser96:N―compound 15 | 2.89 | |||
Thr232:N―compound 15 | 2.92 | π-π interactions | ||||
Thr232:OG1―compound 15 | 2.99 | Tyr180―compound 15 | 4.96 | |||
Gly233:N―compound 15 | 2.89 | Tyr180―compound 15 | 4.16 | |||
Asp209:OD2―compound 15 | 2.08 | |||||
16 | H-bonds | −8.6 | H-bonds | |||
Thr88:N―compound 16 | 3.02 | Asn92:ND2―compound 16 | 2.81 | |||
Thr88:OG1―compound 16 | 2.33 | Ser100:OG―compound 16 | 2.64 | |||
Thr232:N―compound 16 | 2.86 | Lys102:NZ―compound 16 | 2.95 | |||
Thr232: OG1―compound 16 | 2.77 | π-π interactions | ||||
Thr232:OG1―compound 16 | 2.31 | Tyr180―compound 16 | 5.15 | |||
Ser415:OG―compound 16 | 2.89 | Tyr180―compound 16 | 4.28 | |||
17 | H-bonds | −8.1 | ||||
Thr88:N―compound 17 | 2.96 | |||||
Thr88:OG1―compound 17 | 2.82 | H-bonds | ||||
Thr88:OG1―compound 17 | 2.23 | Gly66:O―compound 17 | 2.4 | |||
Thr232:N―compound 17 | 2.99 | Asn92:ND2―compound 17 | 2.97 | |||
Thr232:N―compound 17 | 2.98 | π-π interactions | ||||
Thr232:OG1―compound 17 | 3 | Tyr180―compound 17 | 4.9 | |||
π-cation interactions | Tyr180―compound 17 | 4.13 | ||||
Lys418:NZ―compound 17 | 3.58 | |||||
Lys418:NZ―compound 17 | 4.4 | |||||
18 | H-bonds | −8.0 | ||||
Thr88:N―compound 18 | 3 | |||||
Thr88:OG1―compound 18 | 2.89 | H-bonds | ||||
Thr88:OG1―compound 18 | 2.19 | Asn92:ND2―compound 18 | 3.09 | |||
Thr232:N―compound 18 | 2.99 | Asn92:ND2―compound 18 | 2.89 | |||
Thr232:N―compound 18 | 2.98 | Asp103:OD2―compound 18 | 1.93 | |||
Thr232:OG1―compound 18 | 2.95 | π-π interactions | ||||
Asp413:OD2―compound 18 | 2.37 | Tyr180―compound 18 | 5.03 | |||
π-cation interactions | Tyr180―compound 18 | 4.55 | ||||
Lys418:NZ―compound 18 | 3.63 | |||||
Lys418:NZ―compound 18 | 4.52 | |||||
19 | H-bonds | −8.4 | H-bonds | |||
Thr88:OG1―compound 19 | 2.42 | Asn92:ND2―compound 19 | 2.97 | |||
Asn89:ND2―compound 19 | 2.99 | Ser96:N―compound 19 | 2.95 | |||
Asp413:OD1―compound 19 | 2.4 | Glu97:N―compound 19 | 3.06 | |||
Asp413:OD2―compound 19 | 2.4 | π-π interactions | ||||
Glu446:O―compound 19 | 2.39 | Tyr180―compound 19 | 4.85 | |||
π-sigma interactions | Tyr180―compound 19 | 4.14 | ||||
Gly414:CA―compound 19 | 3.86 | |||||
20 | −7.9 | H-bonds | −10.0 | |||
Thr88:OG1―compound 20 | 2.59 | |||||
Thr88:OG1―compound 20 | 1.79 | H-bonds | ||||
Thr232:N―compound 20 | 2.94 | Tyr180:OH―compound 20 | 2.97 | |||
Thr232:OG1―compound 20 | 2.71 | π-π interactions | ||||
Ser415:OG―compound 20 | 2.73 | Tyr180―compound 20 | 4.34 | |||
Ser415:OG―compound 20 | 2.31 |
Molecular Weight (g/mol) | BBB Permeant | % (HIA+) | logp | TPSA A2 | HBA | HBD | N Rotatable | N Violations | Volume A [3] | GI Absorption | Bioavailability Score | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Reference Range | 130–500 | <25 Poor >80 High | <5 | ≤140 | 2–20 | 0–6 | ≤10 | <5 | 500–2000 | |||
3 | 397.43 | No | 90 | 3.06 | 84.56 | 6 | 1 | 5 | 0 | 354.67 | High | 0.56 |
4 | 411.45 | No | 98 | 2.84 | 84.56 | 6 | 1 | 5 | 0 | 371.26 | High | 0.56 |
5 | 487.55 | No | 97 | 4.30 | 84.56 | 6 | 1 | 7 | 0 | 442.91 | High | 0.56 |
6 | 427.25 | No | 95 | 1.87 | 104.79 | 7 | 2 | 6 | 0 | 379.52 | High | 0.56 |
7 | 503.55 | No | 88 | 3.83 | 104.79 | 7 | 2 | 7 | 1 | 450.39 | High | 0.56 |
8 | 453.53 | No | 91 | 4.15 | 84.56 | 6 | 1 | 7 | 0 | 421.45 | High | 0.56 |
9 | 468.55 | No | 88 | 2.35 | 110.58 | 7 | 3 | 9 | 0 | 433.19 | High | 0.55 |
10 | 454.48 | No | 91 | 2.73 | 127.65 | 8 | 3 | 7 | 0 | 401.77 | High | 0.56 |
11 | 473.53 | No | 96 | 4.44 | 84.56 | 6 | 1 | 6 | 0 | 426.11 | High | 0.56 |
12 | 202.21 | Yes | 73 | 0.26 | 65.45 | 4 | 2 | 3 | 0 | 180.08 | High | 0.85 |
13 | 216.24 | Yes | 87 | 0.04 | 65.45 | 4 | 2 | 3 | 0 | 196.67 | High | 0.85 |
14 | 292.34 | Yes | 81 | 1.50 | 65.45 | 4 | 2 | 5 | 0 | 268.32 | High | 0.85 |
15 | 232.24 | No | 80 | -0.93 | 85.68 | 5 | 3 | 4 | 0 | 204.93 | High | 0.56 |
16 | 308.33 | No | 83 | 1.02 | 85.68 | 5 | 3 | 5 | 0 | 276.34 | High | 0.56 |
17 | 258.32 | Yes | 75 | 1.35 | 65.45 | 4 | 2 | 5 | 0 | 246.86 | High | 0.85 |
18 | 273.43 | No | 85 | -0.45 | 91.48 | 5 | 4 | 7 | 0 | 258.61 | High | 0.55 |
19 | 259.26 | No | 90 | -0.07 | 108.55 | 6 | 4 | 5 | 0 | 227.18 | High | 0.56 |
20 | 278.31 | No | 99 | 2.75 | 65.45 | 4 | 2 | 4 | 0 | 251.52 | High | 0.85 |
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Noser, A.A.; Abdelmonsef, A.H.; El-Naggar, M.; Salem, M.M. New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway. Molecules 2021, 26, 5332. https://doi.org/10.3390/molecules26175332
Noser AA, Abdelmonsef AH, El-Naggar M, Salem MM. New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway. Molecules. 2021; 26(17):5332. https://doi.org/10.3390/molecules26175332
Chicago/Turabian StyleNoser, Ahmed A., Aboubakr H. Abdelmonsef, Mohamed El-Naggar, and Maha M. Salem. 2021. "New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway" Molecules 26, no. 17: 5332. https://doi.org/10.3390/molecules26175332