Selected Drug-Likeness Properties of 2-Arylidene-indan-1,3-dione Derivatives—Chemical Compounds with Potential Anti-Cancer Activity
Abstract
:1. Introduction
2. Results
2.1. Synthesis Mechanism
2.2. Assumptions of the Lipiński’s and Veber’s Rules
2.3. Biological Activity
2.4. Binding to Albumin
2.5. Toxicity
3. Discussion
4. Materials and Methods
4.1. Synthesis, Purification, and Structure Conformation—General Procedure
4.2. Chromatographic Examination of Lipophilicity
4.3. Geometry Optimization of Structures
4.4. Testing of Antiproliferative Activity
4.5. Measurement of the Ability to Bind to Albumin
4.6. Toxicity Simulation
4.7. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
Appendix A
- 2-benzylidene-1H-indene-1,3(2H)-dione (3A)The product was obtained as a yellow powder; 0.645 g (27.53%). m.p. 152–153 °C. C16H10O2 (calcd 234.26). ESI-MS: (M + H)+ = 235.10. 1H-NMR (CDCl3), δ [ppm]: δ 8.45 (m, 2H -Ar), 8.00 (m, 2H -Ar), 7.89 (s, 1H =CH-), 7.80 (m, 2H -Ar), 7.53 (m, 3H -Ar). 13C-NMR (CDCl3), δ [ppm]: 190.43 (aliphatic C in ring), 189.18 (aliphatic C in ring), 147.14 (=CH-), 142.71, 140.24, 135.57, 134.30, 133.34, 129.35, 129.00, 123.50.
- 2-{[4-(dimethylamino)phenyl]methylidene}-1H-indene-1,3(2H)-dione (3B)The product was obtained as a red powder; 1.938 g (69.96%). m.p. 203–205 °C. C18H15NO2 (calcd 277.34). ESI-MS: (M + H)+ = 278.20. 1H-NMR (CDCl3), δ [ppm]: δ 8.51 (d, J = 10 Hz, 2H -Ar), 7.91(m, 2H -Ar), 7.77 (s, 1H =CH-), 7.70 (m, 2H -Ar), 6.73 (d, J = 10 Hz, 2H -Ar), 3.13 (s, 6H -CH3). 13C-NMR (CDCl3), δ [ppm]: 191.27 (aliphatic C in ring), 190.14 (aliphatic C in ring), 154.01, 147.61 (=CH-), 142.40, 138.09, 134.54, 123.31, 122.64, 40.31 (N-CH2).
- 2-(4-methoxybenzylidene)-1H-indene-1,3(2H)-dione (3C)The product was obtained as a red/orange powder; 1.663 g (62.92%); m.p. 156–157 °C. C17H12O3 (calcd 264.29). ESI-MS: (M + H)+ = 265.15. 1H-NMR (CDCl3), δ [ppm]: δ 8.52 (d, J = 10 Hz, 2H -Ar), 7.96 (m, 2H -Ar), 7.82 (s, =CH-), 7.76 (m, 2H -Ar), 6.99 (m, 2H -Ar), 3.89 (s, -CH3). 13C-NMR (CDCl3), δ [ppm]: 190.95 (aliphatic C in ring), 189.65 (aliphatic C in ring), 164.20, 146.97 (=CH-), 142.53, 140.12, 137.34, 135.09, 126.67, 123.21, 114.52, 55.73 (-OCH3).
- 2-{[4-(4-methylphenoxy)phenyl]methylidene}-1H-indene-1,3(2H)-dione (3D)The product was obtained as a yellow powder; 0.518 g (60.99%); m.p. 146–147 °C. C23H16O3 (calcd 340.39). ESI-MS: (M + H)+ = 341.20. 1H-NMR (CDCl3), δ [ppm]: δ 8.54 (d, J = 10 Hz, 2H -Ar), 8.01 (m, 2H -Ar), 7.88 (s, =CH-), 7.83 (m, 2H -Ar), 7.25 (m, 2H -Ar), 7.05 (m, 4H -Ar), 2.4 (s, -CH3). 13C-NMR (CDCl3), δ [ppm]: 190.78 (aliphatic C in ring), 189.48 (aliphatic C in ring), 163.09, 152.77, 146.53 (=CH-), 142.55, 140.14, 135.29, 135.09, 134.81, 130.73, 127.74, 120.58, 117.25, 20.96 (CH3).
- 2-[(3-hydroxy-4-methoxyphenyl)methylidene]-1H-indene-1,3(2H)-dione (3E)The product was obtained as a lemon powder; 2.084 g (74.35%); m.p. 227–228 °C. C17H12O4 (calcd 280.29). ESI-MS: (M + H)+ = 281.15. 1H-NMR (CDCl3), δ [ppm]: δ 8.27 (s, 1H = CH-), 8.06 (m, 1H -Ar), 7.98 (m, 2H -Ar), 7.77 (m, 2H -Ar), 6.96 (d, J = 5 Hz, 1H -Ar), 5.66 (s, 1H -Ar), 3.99 (s, 3H -Ar), 3.85 (s, 1H -OH). 13C-NMR (CDCl3), δ [ppm]: 190.90 (aliphatic C in ring), 189.46 (aliphatic C in ring), 151.40, 147.28, 145.61 (=CH-), 142.63, 140.14, 135.28, 135.04, 123.31, 123.26, 110.53, 56.30 (-CH3).
- 2-[(naphthalen-1-yl)methylidene]-1H-indene-1,3(2H)-dione (3F)The product was obtained as an orange powder; 0.883 g (62.10%); m.p. 175–176 °C. C20H12O2 (calcd 284.32). ESI-MS: (M + H)+ = 285.10. 1H-NMR (CDCl3), δ [ppm]: δ 8.78 (s, =CH-), 8.74 (d, J = 10 Hz, 1H -Ar), 8.24 (d, J = 10 Hz, 1H -Ar), 8.02 (m, 3H -Ar), 7.91 (d, J = 5 Hz, 1H -Ar), 7.81 (m, 2H -Ar), 7.62 (m, 2H -Ar), 7.55 (t, J = 5 Hz, 1H -Ar). 13C-NMR (CDCl3), δ [ppm]: 190.32 (aliphatic C in ring), 188.81 (aliphatic C in ring), 143.22, 142.69, 140.23 (=CH-), 135.60, 135.43, 133.73, 133.66, 132.89, 132.22, 130.24, 129.29, 128.76, 127.80, 126.48, 125.30, 123.76, 123.53.
- 2-[(4,7-dimethoxynaphthalen-1-yl)methylidene]-1H-indene-1,3(2H)-dione (3G)The product was obtained as a brown-beige powder; 1.305 g (37.89%); m.p. 223–225 °C. C22H16O4 (calcd 344.38). ESI-MS: (M + H)+ = 345.15. 1H-NMR (CDCl3), δ [ppm]: δ 9.20 (d, J = 5 Hz, 1H -Ar), 8.68 (s, 1H =CH-), 8.24 (d, J = 10 Hz, 1H -Ar), 7.99 (m, 2H -Ar), 7.77 (m, 2H -Ar), 7.54 (s, 1H -Ar), 7.15 (d, J = 5 Hz, 1H -Ar), 6.87 (d, J = 5 Hz, 1H -Ar), 4.09 (s, 3H -CH3), 4.00 (s, 3H -CH3). 13C-NMR (CDCl3), δ [ppm]: 191.31 (aliphatic C in ring), 189.49 (aliphatic C in ring), 161.23, 160.06, 143.04, 142.53 (=CH-), 140.00, 136.83, 135.12, 134.90, 126.69, 125.08, 123.15, 123.07, 120.86, 120.56, 117.71, 102.69, 56.12 (-OCH3), 55.67 (-OCH3).
- 2-[(furan-3-yl)methylidene]-1H-indene-1,3(2H)-dione (3H)The product was obtained as a brown powder; 0.612 g (27.30%); m.p. 152–153 °C. C14H8O3 (calcd 224.22). ESI-MS: (M + H)+ = 225.10. 1H-NMR (CDCl3), δ [ppm]: δ 8.64 (s, 1H =CH-), 7.97 (m, 2H -Ar), 7.78 (m, 2H -Ar), 7.72 (s, 1H furan ring), 7.52 (m, 1H furan ring), 7.38 (m, 1H furan ring). 13C-NMR (CDCl3), δ [ppm]: 190.34 (aliphatic C in ring), 189.53 (aliphatic C in ring), 152.45, 144.53, 142.48, 140.40, 135.40, 135.18 (=CH-), 135.00, 127.76, 123.39, 123.24, 121.99, 113.08.
- 2-{[4-(diphenylamino)phenyl]methylidene}-1H-indene-1,3(2H)-dione (3I)The product was obtained as a brick-red powder; 1.617 g (80.57%); m.p. 211–212 °C. C28H19NO2 (calcd 401.48). ESI-MS: (M + H)+ = 402.20. 1H-NMR (CDCl3), δ [ppm]: δ 8.40 (d, J = 10 Hz, 2H -Ar), 7.96 (m, 2H -Ar), 7.80 (s, 1H =CH-), 7.77 (m, 2H -Ar), 7.38 (m, 2 × 2H -Ar), 7.22 (m, 2 × 3H -Ar), 7.03 (d, J = 10 Hz, 2H -Ar). 13C-NMR (CDCl3), δ [ppm]: 191.41 (aliphatic C in ring), 189.79 (aliphatic C in ring), 152.87, 146.73, 145.91, 142.52, 140.13, 136.95, 134.92, 134.68, 129.90, 126.71, 125.65, 122.99, 122.96, 119.02.
- 2-[(4-hydroxyphenyl)methylidene]-1H-indene-1,3(2H)-dione (3J)The product was obtained as a red powder; 0.980 g (78.40%); m.p. 238–240 °C. C16H10O3 (calcd 250.26). ESI-MS: (M + H)+ = 251.10. 1H-NMR (DMSO-d6), δ [ppm]: δ 6.94 (d, J = 14 Hz, 2H -Ar); 7.74 (s, 1H =CH); 7.92 (m, 4H -Ar); 8.53 (d, J = 14 Hz, 2H -Ar); 10.91 (s, 1H -OH). 13C-NMR (DMSO-d6), δ [ppm]: 189.98 (aliphatic C in ring), 189.02 (aliphatic C in ring), 163.31, 146.30 (=CH-), 141.66, 137.60, 135.55, 135.38, 122.75, 122,70, 116.00.
- 2-[(6-hydroxy-2H-1-benzopyran-3-yl)methylidene]-1H-indene-1,3(2H)-dione (3K)The product was obtained as a brown-black powder; 0.116 g (15.24%); m.p. > 260 °C. C19H12O4 (calcd 304.31). ESI-MS: (M + H)+ = 305.1. 1H-NMR (DMSO-d6), δ [ppm]: δ 5.33 (s, 2H); 6.70 (s, 1H -Ar); 6.76 (d, J = 1.4 Hz, 2H -Ar); 7.40 (s, 1H -Ar); 7.71 (s, 1H =CH); 7.94 (m, 4H -Ar), 9.31 (s, 1H -OH). 13C-NMR (DMSO-d6), δ [ppm]: 189.35 (aliphatic C in ring), 188.55 (aliphatic C in ring), 152.05, 148.25, 142.62 (=CH-), 140.86, 135.79, 130.08, 122.93, 122.85, 116.58, 114.34, 66.55.
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Lipiński’s Rule | Veber’s Rule | ||
---|---|---|---|
Feature | Value | Feature | Value |
LogP | <5 | number of rotating bonds (RotB) | ≤10 |
molecular weight (MW) | <500 Da | ||
number of hydrogen bond acceptors (AHB) | <10 | polar surface area (PSA) | <140 Å2 |
number of hydrogen bond donors (DHB) | <5 |
Compound | MeOH | ACN | Δ * | ||||
---|---|---|---|---|---|---|---|
logkw | R2 | −S | logkw | R2 | −S | ||
3A | 3.3210 | 0.9907 | 3.3278 | 2.2433 | 0.9974 | 2.4449 | 1.0777 |
3B | 3.2790 | 0.9955 | 3.1597 | 2.2394 | 0.9982 | 2.3613 | 1.0396 |
3C | 3.3554 | 0.9968 | 3.2782 | 2.3042 | 0.9976 | 2.4879 | 1.0512 |
3D | 5.6763 | 0.9966 | 5.4798 | 3.5726 | 0.9993 | 3.5570 | 2.1037 |
3E | 2.2321 | 0.9917 | 2.4114 | 1.5356 | 0.9919 | 1.9201 | 0.6965 |
3F | 3.9640 | 0.9967 | 3.8549 | 2.6107 | 0.9987 | 2.7449 | 1.3533 |
3G | 4.6064 | 0.9972 | 4.6064 | 2.8533 | 0.9991 | 2.8762 | 1.7531 |
3H | 2.5521 | 0.9959 | 2.6243 | 1.9162 | 0.9950 | 2.2011 | 0.6359 |
3I | 5.3524 | 0.9994 | 5.0483 | 3.8489 | 0.9995 | 3.7589 | 1.5035 |
3J | 2.3814 | 0.9952 | 2.5802 | 3.7694 | 0.9997 | 3.7694 | 1.3880 |
3K | 2.9717 | 0.9946 | 3.0667 | 1.7720 | 0.9967 | 2.1213 | 1.1997 |
Compound | MLOGP * | ALOGP ** | LogP o/w *** |
---|---|---|---|
3A | 3.322 | 3.236 | 3 |
3B | 3.235 | 3.399 | 3 |
3C | 2.998 | 3.22 | 2.99 |
3D | 4.402 | 5.283 | 4.6 |
3E | 2.458 | 2.953 | 2.61 |
3F | 4.116 | 4.145 | 3.91 |
3G | 3.451 | 4.112 | 3.89 |
3H | 1.664 | 2.34 | 2.31 |
3I | 5.218 | 6.569 | 5.45 |
3J | 2.754 | 2.969 | 2.58 |
3K | 2.462 | 3.134 | 2.76 |
Compound | LD50 * | Toxicity Class ** |
---|---|---|
3A | 1113.0 | harmful |
3B | 1707.0 | harmful |
3C | 3167.0 | unclassified |
3D | 2937.0 | unclassified |
3E | 2608.0 | unclassified |
3F | 742.5 | harmful |
3G | 1707.0 | harmful |
3H | 1264.0 | harmful |
3I | 2176.0 | unclassified |
3J | 2373.0 | unclassified |
3K | 577.4 | harmful |
indan-1,3-dione | 297.8 | harmful |
doxorubicin | 110.8 | toxic |
Compound | Acute Toxicity [mg/L] | Overcoming the Blood–Brain Barrier * | Carcinogenicity ** | Mutagenicity *** | |
---|---|---|---|---|---|
Fathead minnow | Daphnia magna | ||||
3A | 0.236 | 6.58 | penetrating | non-carcinogenic | mutagenic |
3B | 21.4 | 9.65 | non-penetrating | carcinogenic | non-mutagenic |
3C | 32.1 | 3.59 | non-penetrating | non-carcinogenic | mutagenic |
3D | 69.8 | 42.2 | penetrating | non-carcinogenic | mutagenic |
3E | 31.7 | 9.4 | non-penetrating | non-carcinogenic | mutagenic |
3F | 4.51 | 2.82 | non-penetrating | non-carcinogenic | mutagenic |
3G | 64.5 | 9.3 | penetrating | carcinogenic | mutagenic |
3H | - **** | - **** | penetrating | non-carcinogenic | non-mutagenic |
3I | - **** | 10.6 | non-penetrating | non-carcinogenic | mutagenic |
3J | 13.7 | 12.3 | penetrating | non-carcinogenic | mutagenic |
3K | 24.4 | 23.4 | non-penetrating | non-carcinogenic | mutagenic |
indan-1,3-dione | 52.9 | 25.7 | penetrating | non-carcinogenic | non-mutagenic |
Doxorubicin | - ***** | - ***** | non-penetrating | carcinogenic | mutagenic |
1 2A–2K 3A–3K 4 | ||
A | B | C |
D | E | F |
G | H | I |
substrate | ||
product | ||
J * | K |
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Pluskota, R.; Jaroch, K.; Kośliński, P.; Ziomkowska, B.; Lewińska, A.; Kruszewski, S.; Bojko, B.; Koba, M. Selected Drug-Likeness Properties of 2-Arylidene-indan-1,3-dione Derivatives—Chemical Compounds with Potential Anti-Cancer Activity. Molecules 2021, 26, 5256. https://doi.org/10.3390/molecules26175256
Pluskota R, Jaroch K, Kośliński P, Ziomkowska B, Lewińska A, Kruszewski S, Bojko B, Koba M. Selected Drug-Likeness Properties of 2-Arylidene-indan-1,3-dione Derivatives—Chemical Compounds with Potential Anti-Cancer Activity. Molecules. 2021; 26(17):5256. https://doi.org/10.3390/molecules26175256
Chicago/Turabian StylePluskota, Robert, Karol Jaroch, Piotr Kośliński, Blanka Ziomkowska, Agnieszka Lewińska, Stefan Kruszewski, Barbara Bojko, and Marcin Koba. 2021. "Selected Drug-Likeness Properties of 2-Arylidene-indan-1,3-dione Derivatives—Chemical Compounds with Potential Anti-Cancer Activity" Molecules 26, no. 17: 5256. https://doi.org/10.3390/molecules26175256