Tumor-Specificity, Neurotoxicity, and Possible Involvement of the Nuclear Receptor Response Pathway of 4,6,8-Trimethyl Azulene Amide Derivatives
Abstract
:1. Introduction
2. Results
2.1. Tumor-Specificity
2.2. Apoptosis-Inducing Activity
2.3. Neurotoxicity
2.4. Computational Analysis
2.5. Possible Nuclear Receptor/Stress Response Pathways
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Synthesis of Alkylamidoazulene Groups
4.3. Cell Culture
4.4. Synthesis Assay for Cytotoxic Activity
4.5. Calculation of Tumor-Selectivity Index (TS)
4.6. Calculation of Potency-Selectivity Expression (PSE)
4.7. Western Blot Analysis
4.8. Cell Cycle Analysis
4.9. Calculation of Chemical Descriptors
4.10. Calculation of Chemical Descriptors
4.11. Statistical Analysis
5. 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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CC50 (μM) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Human Oral Squamous Cell Carcinoma Cells | Human Normal Oral Cells | ||||||||||||
Ca9-22 | HSC-2 | HSC-3 | HSC-4 | Mean | HGF | HPLF | HPC | Mean | TS | PSE | |||
(A) | (B) | (C) | (D) | (D/B) | (C/A) | 100D/B2 | 100C/A2 | ||||||
1 | 335.1 | 400.0 | 397.4 | 400.0 | 383.1 | 400.0 | 400.0 | 400.0 | 400.0 | 1.0 | 1.2 | 0.3 | 0.4 |
2 | 379.3 | 377.8 | 400.0 | 400.0 | 389.3 | 400.0 | 400.0 | 400.0 | 400.0 | 1.0 | 1.1 | 0.3 | 0.3 |
3 | 233.4 | 400.0 | 400.0 | 377.8 | 352.8 | 400.0 | 400.0 | 400.0 | 400.0 | 1.1 | 1.7 | 0.3 | 0.7 |
4 | 288.1 | 313.8 | 361.0 | 375.6 | 334.6 | 400.0 | 391.6 | 376.9 | 389.5 | 1.2 | 1.4 | 0.3 | 0.5 |
5 | 53.5 | 40.8 | 63.2 | 106.5 | 66.0 | 293.3 | 363.9 | 181.9 | 279.7 | 4.2 | 5.5 | 6.4 | 10.2 |
6 | 71.1 | 86.9 | 59.0 | 196.9 | 103.5 | 400.0 | 400.0 | 400.0 | 400.0 | 3.9 | 5.6 | 3.7 | 7.9 |
7 | 41.6 | 55.1 | 38.9 | 62.9 | 49.6 | 400.0 | 356.9 | 400.0 | 385.6 | 7.8 | 9.6 | 15.7 | 23.1 |
8 | 46.7 | 52.4 | 46.3 | 60.1 | 51.4 | 354.9 | 266.8 | 328.0 | 316.6 | 6.2 | 7.6 | 12.0 | 16.2 |
9 | 29.3 | 33.9 | 33.8 | 35.2 | 33.0 | 298.2 | 156.1 | 112.5 | 189.0 | 5.7 | 10.2 | 17.3 | 34.8 |
10 | 124.2 | 337.0 | 181.3 | 328.7 | 242.8 | 400.0 | 400.0 | 400.0 | 400.0 | 1.7 | 3.2 | 0.7 | 2.6 |
11 | 55.9 | 76.5 | 46.3 | 81.6 | 65.1 | 400.0 | 355.6 | 400.0 | 385.2 | 5.9 | 7.2 | 9.1 | 12.8 |
12 | 110.7 | 162.7 | 101.3 | 155.6 | 132.6 | 303.2 | 270.7 | 168.0 | 247.3 | 1.9 | 2.7 | 1.4 | 2.5 |
13 | 120.5 | 173.1 | 73.6 | 153.6 | 130.2 | 327.7 | 293.0 | 201.6 | 274.1 | 2.1 | 2.7 | 1.6 | 2.3 |
14 | 391.1 | 377.8 | 309.4 | 400.0 | 369.6 | 400.0 | 400.0 | 400.0 | 400.0 | 1.1 | 1.0 | 0.3 | 0.3 |
15 | 19.9 | 16.8 | 29.4 | 21.5 | 21.9 | 400.0 | 400.0 | 377.8 | 392.6 | 17.9 | 20.1 | 81.7 | 101.0 |
DOX | 0.4 | 0.2 | 0.4 | 0.1 | 0.3 | 10.0 | 9.0 | 10.0 | 9.7 | 34.5 | 25.1 | 12,325.0 | 6270.0 |
5-FU | 191.2 | 703.0 | 673.5 | 33.1 | 400.2 | 1000.0 | 1000.0 | 1000.0 | 1000.0 | 2.5 | 5.2 | 0.6 | 2.7 |
L-PAM | 34.7 | 11.9 | 20.1 | 6.9 | 18.4 | 200.0 | 200.0 | 173.4 | 191.1 | 10.4 | 5.8 | 56.5 | 16.6 |
CC50 (μM) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Exp. 1 | Exp. 2 | Exp. 3 | |||||||||||
PC12 | SH-SY5Y | LYPPB6 | Mean | PC12 | SH-SY5Y | LYPPB6 | Mean | dPC12 | Normal Cells | NT 1 | |||
(E) | (F) | (G) | (D) | (D/E) | (D/F) | (D/G) | |||||||
7 | 59 | 400 | 400 | 286 | 68 | 400 | 400 | 289 | 400 | 386 | 1.4 | 1.3 | 1.0 |
9 | 35 | 73 | 56 | 55 | 36 | 63 | 74 | 58 | 19 | 189 | 3.5 | 3.3 | 10.2 |
15 | 378 | 42 | 400 | 273 | 400 | 400 | 400 | 400 | 400 | 393 | 1.4 | 1.0 | 1.0 |
DOX | 0.07 | 0.02 | 0.32 | 0.14 | 0.26 | 0.12 | 0.78 | 0.39 | 0.22 | 10 | 70.6 | 25.0 | 44.9 |
5-FU | 14 | 5.85 | 250 | 89.95 | 2 | 1 | 125 | 43 | 297 | 1000 | 11.0 | 23.3 | 3.4 |
L-PAM | N.D. | N.D. | N.D. | N.D. | 2 | 2 | 25 | 10 | 26 | 191 | N.D. | 19.8 | 7.2 |
Important Descriptors | Significance of Correlation with T-N | Meanings |
---|---|---|
AATSC0v | r2 = 0.707; p = 0.0000853 | Autocorrelation of Topological Structure of lag 0 atoms weighted by van der Waals volume |
GATS1s | r2 = 0.694; p = 0.000114 | Autocorrelation of Topological Structure of lag 1 atoms weighted by Sanderson EN |
FASA_H | r2 = 0.671; p = 0.000185 | Descriptor related to water accessible surface area of all hydrophobic atoms |
FASA_P | r2 = 0.671; p = 0.000185 | Descriptor related to water accessible surface area of all polar atoms |
GATS4s | r2 = 0.669; p = 0.000196 | Autocorrelation of Topological Structure of lag 4 atoms weighted by intrinsic state |
vsurf_CW5 | r2 = 0.668; p = 0.00020 | Capacity factor |
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Naitoh, K.; Orihara, Y.; Sakagami, H.; Miura, T.; Satoh, K.; Amano, S.; Bandow, K.; Iijima, Y.; Kurosaki, K.; Uesawa, Y.; et al. Tumor-Specificity, Neurotoxicity, and Possible Involvement of the Nuclear Receptor Response Pathway of 4,6,8-Trimethyl Azulene Amide Derivatives. Int. J. Mol. Sci. 2022, 23, 2601. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052601
Naitoh K, Orihara Y, Sakagami H, Miura T, Satoh K, Amano S, Bandow K, Iijima Y, Kurosaki K, Uesawa Y, et al. Tumor-Specificity, Neurotoxicity, and Possible Involvement of the Nuclear Receptor Response Pathway of 4,6,8-Trimethyl Azulene Amide Derivatives. International Journal of Molecular Sciences. 2022; 23(5):2601. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052601
Chicago/Turabian StyleNaitoh, Kotone, Yuta Orihara, Hiroshi Sakagami, Takumi Miura, Keitaro Satoh, Shigeru Amano, Kenjiro Bandow, Yosuke Iijima, Kota Kurosaki, Yoshihiro Uesawa, and et al. 2022. "Tumor-Specificity, Neurotoxicity, and Possible Involvement of the Nuclear Receptor Response Pathway of 4,6,8-Trimethyl Azulene Amide Derivatives" International Journal of Molecular Sciences 23, no. 5: 2601. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052601