Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. Synthesis of Isophthaloyl and Terephthaloyl Dichlorides 3 and 4
2.1.2. General Method for the Synthesis of Compounds 5–28
2.2. Cell Proliferation Assay
2.3. Kinase Inhibitory Assay
2.4. Cell Apoptosis Assay
2.5. In Vitro Cell Cycle Effects
2.6. ROS Determination
2.7. Molecular Docking and Molecular Dynamics
3. Results and Discussion
3.1. Molecular Design
3.2. Chemistry
3.3. Biological Studies
3.3.1. Antiproliferative Activity
3.3.2. Kinase Inhibitory Assays
3.3.3. In Vitro Cell Cycle Effects of Compounds 5, 14 and 15
3.3.4. Apoptosis Assay
3.3.5. Reactive Oxygen Species (ROS)
3.4. Docking and Molecular Dynamics
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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R1 | R2 | Isophthalic Derivatives | Terephthalic Derivatives | ||||
---|---|---|---|---|---|---|---|
No. | Structure | Yield, % | No. | Structure | Yield, % | ||
a | b | 5 | 15 | 17 | 20 | ||
a | c | 6 | 23 | 18 | 10 | ||
a | e | 7 | 15 | 19 | 16 | ||
a | f | 8 | 57 | 20 | 35 | ||
a | g | 9 | 44 | 21 | 50 | ||
b | b | 10 | 14 | 22 | 27 | ||
b | c | 11 | 11 | 23 | 12 | ||
b | d | 12 | 13 | 24 | 20 | ||
b | e | 13 | 10 | 25 | 14 | ||
b | f | 14 | 25 | 26 | 18 | ||
b | g | 15 | 17 | 27 | 12 | ||
c | d | 16 | 9 | 28 | 10 |
Comp. | Acid | R1 | R2 | Anti-Proliferative Activities in Deferent Cell Lines (IC50 µM) 1 | ||||||
---|---|---|---|---|---|---|---|---|---|---|
K562 | HL-60 | MCF-7 | HepG2 | A549 | OKP-GS | RPMI 1788 | ||||
5 | Iso | a | b | 3.42 ± 0.78 | 7.04 ± 0.29 | 4.91 ± 1.27 | 7.84 ± 2.61 | >50 | 17.76 ± 2.13 | 2.86 ± 0.09 |
6 | Iso | a | c | >50 | >50 | 41.15 ± 5.06 | >50 | >50 | >50 | 12.98 ± 2.99 |
8 | Iso | a | f | 18.33 ± 1.15 | 18.19 ± 1.02 | 24.71 ± 5.95 | 35.49 ± 0.34 | >50 | >50 | 24.91 ± 1.17 |
9 | Iso | a | g | 20.99 ± 0.59 | 21.90 ± 1.59 | 26.29 ± 3.71 | 33.29 ± 3.45 | >50 | >50 | 26.26 ± 1.88 |
10 | Iso | b | b | 25.96 ± 2.38 | 35.75 ± 3.19 | 38.47 ± 1.95 | 23.21 ± 1.81 | >50 | 13.23 ± 1.30 | 13.00 ± 0.30 |
11 | Iso | b | c | >50 | >50 | >50 | >50 | >50 | 26.51 ± 3.65 | 21.89 ± 0.44 |
12 | Iso | b | d | >50 | >50 | >50 | >50 | >50 | 27.47 ± 2.58 | 2.36 ± 1.13 |
14 | Iso | b | f | 7.71 ± 2.84 | 32.50 ± 1.50 | 27.30 ± 0.16 | 44.09 ± 4.19 | >50 | >50 | 26.63 ± 2.31 |
15 | Iso | b | g | 10.51 ± 2.54 | 34.76 ± 4.70 | 27.38 ± 0.26 | 45.81 ± 1.76 | >50 | >50 | 29.40 ± 1.79 |
17 | Tere | a | b | 15.62 ± 0.00 | >50 | >50 | >50 | >50 | >50 | >50 |
18 | Tere | a | c | 26.93 ± 0.00 | >50 | >50 | 45.85 ± 1.83 | >50 | 34.43 ± 2.52 | 46.02 ± 1.76 |
19 | Tere | a | e | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
20 | Tere | a | f | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
21 | Tere | a | g | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
22 | Tere | b | b | >50 | >50 | >50 | >50 | >50 | >50 | >50 |
24 | Tere | b | d | 16.98 ± 0.20 | 26.42 ± 3.35 | 15.48 ± 1.16 | >50 | >50 | >50 | 36.49 ± 0.86 |
26 | Tere | b | f | 18.53 ± 0.73 | 26.41 ± 1.73 | 48.83 ± 1.17 | 44.28 ± 4.79 | >50 | >50 | 23.97 ± 0.03 |
27 | Tere | b | g | 22.25 ± 2.12 | 26.04 ± 4.15 | 49.36 ± 0.67 | 38.63 ± 1.11 | >50 | >50 | 24.08 ± 0.07 |
Reference Compounds | ||||||||||
Sorafenib | 2.44 ± 0.21 | 3.37 ± 0.42 | 8.62 ± 2.24 | 5.01 ± 0.14 | 12.52 ± 1.64 | 7.17 ± 0.50 | 3.48 ± 0.39 | |||
Nilotinib | <0.1 | 22.67 ± 4.76 | 4.20 ± 0.14 | 4.81 ± 0.21 | >50 | 2.76 ± 0.06 | 19.32 ± 0.09 | |||
Lapatinib | 9.62 ± 1.56 | 10.58 ± 1.02 | 10.93 ± 0.34 | 27.10 ± 0.08 | 18.55 ± 2.65 | 7.32 ± 2.15 | 9.31 ± 0.90 |
Kinase | % Inhibition at 10 µM | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Lapat. | Soraf. | Sunit. | 5 | 8 | 9 | 10 | 14 | 17 | 19 | 24 | |
Tyrosine Kinases | |||||||||||
EGFR | 100 | 0 | - | 0 | 14 | 90 | 1 | 21 | 0 | 4 | 2 |
HER2 | 76 | 0 | - | 33 | 0 | 64 | 19 | 14 | 13 | 39 | 49 |
HER4 | 100 | 0 | - | 0 | 0 | 37 | 0 | 0 | 0 | 2 | 3 |
IGF1R | 0 | 0 | - | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
InsR | 0 | 0 | - | 0 | 6 | 0 | 0 | 0 | 0 | 17 | 0 |
KDR | 24 | 100 | - | 18 | 34 | 33 | 33 | 26 | 0 | 16 | 0 |
PDGFRα | 2 | 100 | - | 73 | 0 | 20 | 17 | 24 | 20 | 19 | 0 |
PDGFRβ | 10 | 100 | - | 18 | 0 | 24 | 0 | 23 | 15 | 20 | 0 |
Serine/Threonine Kinases | |||||||||||
Aurora A | - | - | 68 | 0 | 0 | 0 | 0 | 0 | 0 | - | 0 |
Aurora B | - | - | 90 | 0 | 0 | 0 | 0 | 7 | 0 | - | 3 |
Comp. | Concentration, µM | G1, % | S, % | G2/M, % | Apoptosis, % |
---|---|---|---|---|---|
K562 (control) | 31.11 | 23.27 | 45.62 | 14.80 | |
5 | 1 | 37.92 | 17.01 | 45.08 | 14.56 |
5 | 31.77 | 18.14 | 50.09 | 37.20 | |
10 | 29.86 | 32.05 | 38.08 | 53.50 | |
14 | 1 | 32.65 | 20.41 | 46.95 | 14.28 |
5 | 27.58 | 17.25 | 55.16 | 25.10 | |
10 | 31.21 | 17.71 | 51.08 | 38.02 | |
15 | 1 | 30.15 | 21.31 | 48.54 | 17.90 |
5 | 34.76 | 11.59 | 53.65 | 20.54 | |
10 | 28.85 | 8.16 | 62.99 | 32.72 | |
Lap. | 1 | 34.47 | 13.31 | 52.23 | 14.74 |
5 | 31.31 | 13.02 | 55.68 | 28.92 | |
Sor. | 1 | 36.50 | 7.72 | 55.78 | 22.60 |
5 | 33.87 | 30.14 | 35.99 | 44.20 |
Concentration, µM | Control | ROS Level, % of Control | ||||
---|---|---|---|---|---|---|
Compound | ||||||
5 | 14 | 15 | Sor. | Lap. | ||
5 | 100% | 76.76 | 92.84 | 92.89 | 69.20 | 64.12 |
10 | 64.66 | 76.96 | 87.87 | 79.03 | 72.23 | |
20 | 62.90 | 71.90 | 94.07 | 71.59 | 89.07 |
Protein Family | PDB Code | Linker | N Comp. | Gmx_Mmpbsa, kcal/mol | RF- Score | g_mmpbsa, kJ/mol | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
v.d.w. | Electr. | Entr. | Total | v.d.w. | Electr. | Total | |||||
ABL | 3cs9 | iso | 7 | −68 | −21.6 | 13.8 | −46 | 6.1 | −284.4 | −43.96 | −141.8 |
ABL | 3cs9 | iso | 8 | −62.6 | −14 | 13.2 | −41 | 6.2 | −262 | −29.21 | −128.6 |
ABL | 3cs9 | iso | 11 | −77.1 | −37.1 | 9.1 | −47.9 | 6.3 | −322.3 | −77.15 | −144.4 |
ABL | 3cs9 | iso | 14 | −72.6 | −13.5 | 6 | −53.3 | 6.3 | −303.5 | −28.01 | −144.9 |
TRKC | 6kzd | iso | 8 | −59.3 | −2.4 | 13.3 | −34.5 | 6.0 | −248 | −5.111 | −123.5 |
TRKC | 6kzd | iso | 9 | −48.5 | −30.7 | 14.4 | −21.5 | 6.0 | −202.8 | −64.39 | −76.8 |
TRKC | 6kzd | iso | 13 | −65.8 | −40.7 | 17.8 | −31.4 | 6.3 | −275.3 | −85.14 | −95.59 |
TRKC | 6kzd | iso | 14 | −62.7 | −4.4 | 16.2 | −31.4 | 6.1 | −262.3 | −9.205 | −111.5 |
TRKC | 6kzd | iso | 15 | −70.1 | −20 | 9.9 | −45.6 | 6.2 | −293.4 | −41.89 | −137.9 |
TRKC | 6kzd | tere | 21 | −58.1 | −29.8 | 8.6 | −39.3 | 6.0 | −243.1 | −62.39 | −128.4 |
TRKC | 6kzd | tere | 25 | −69.8 | −22.4 | 14.2 | −37 | 6.2 | −291.8 | −46.92 | −149 |
TRKC | 6kzd | tere | 26 | −69.6 | −19 | 18.7 | −38.8 | 6.2 | −291.3 | −39.37 | −141.1 |
TRKC | 6kzd | tere | 27 | −63.8 | −5.5 | 15.2 | −27.4 | 6.2 | −266.7 | −11.69 | −125.9 |
VEGFR1 | 3hng | iso | 5 | −64.9 | −22.6 | 16 | −36.8 | 6.3 | −271.3 | −47.31 | −119.6 |
VEGFR2 | 4ag8 | iso | 5 | −65.4 | −23.2 | 11.2 | −44 | 6.2 | −273.6 | −49.12 | −138.8 |
VEGFR2 | 4ag8 | iso | 7 | −65.2 | −33.1 | 7.7 | −58 | 6.2 | −272.9 | −69.09 | −148.4 |
VEGFR2 | 4ag8 | iso | 11 | −76.4 | −34.4 | 9.3 | −53.5 | 6.5 | −319.5 | −71.87 | −150.8 |
VEGFR2 | 3wze | iso | 11 | −71.1 | −26.2 | 9.9 | −48.8 | 6.5 | −297.4 | −54.7 | −150.5 |
VEGFR2 | 4asd | iso | 11 | −79.9 | −33.8 | 10.1 | −53.6 | 6.5 | −334.2 | −70.75 | −155.3 |
VEGFR2 | 3wze | iso | 14 | −74 | −30.8 | 7.4 | −64 | 6.5 | −309.6 | −64.57 | −157.0 |
VEGFR2 | 3wze | tere | 21 | −51.9 | −30.3 | 8 | −34.7 | 6.0 | −217 | −63.19 | −85.65 |
BRAF | 5hi2 | iso | 8 | −57.4 | −27.4 | 7 | −46.6 | 6.1 | −240.2 | −57.45 | −118.9 |
ERBB2 | 3pp0 | iso | 9 | −55.6 | −9.1 | 7.7 | −34.1 | 6.0 | −232.6 | −19.04 | −96.72 |
ERBB2 | 3pp0 | tere | 20 | −50.8 | −15.6 | 11.5 | −26.7 | 6.0 | −212.6 | −32.59 | −86.55 |
ERBB4 | 3bbt | iso | 14 | −50.4 | −22.4 | 8.6 | −30.7 | 6.0 | −211.0 | −46.8 | −79.0 |
Reference ligands | |||||||||||
ABL | 2hyy | imatinib | −67.4 | −20.1 | 5.3 | −50.5 | 6.2 | −282.1 | −42.4 | −154.7 | |
ABL | 3cs9 | nilotinib | −72.8 | −28.1 | 6.1 | −56.1 | 6.6 | −304.6 | −57.8 | −183.1 | |
VEGFR2 | 3wze | sorafenib | −60.8 | −35.3 | 7.4 | −58.5 | 6.2 | −254.3 | −73.9 | −170.0 | |
VEGFR2 | 4asd | sorafenib | −60.3 | −37.9 | 5.9 | −59.8 | 6.2 | −252.2 | −79.3 | −153.0 | |
ERBB4 | 3bbt | lapatinib | −58.7 | −26.5 | 6.2 | −54.4 | 6.1 | −245.6 | −55.2 | −179.8 | |
TRKC | 6kzd | not approved | −82.6 | −31.7 | 8.2 | −61.0 | 6.4 | −345.5 | −66.2 | −206.9 |
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Kalinichenko, E.; Faryna, A.; Bozhok, T.; Golyakovich, A.; Panibrat, A. Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity. Curr. Issues Mol. Biol. 2023, 45, 1820-1842. https://doi.org/10.3390/cimb45030117
Kalinichenko E, Faryna A, Bozhok T, Golyakovich A, Panibrat A. Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity. Current Issues in Molecular Biology. 2023; 45(3):1820-1842. https://doi.org/10.3390/cimb45030117
Chicago/Turabian StyleKalinichenko, Elena, Aliaksandr Faryna, Tatyana Bozhok, Anna Golyakovich, and Alesya Panibrat. 2023. "Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity" Current Issues in Molecular Biology 45, no. 3: 1820-1842. https://doi.org/10.3390/cimb45030117
APA StyleKalinichenko, E., Faryna, A., Bozhok, T., Golyakovich, A., & Panibrat, A. (2023). Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity. Current Issues in Molecular Biology, 45(3), 1820-1842. https://doi.org/10.3390/cimb45030117