Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of the Reference and Hybrid Impiridones
2.2. NMR Analysis of the Skeletal Structure of Novel Impiridones
2.3. DFT Analysis of the Simplified Model Impiridones Carrying 2-Iodoferrocenylmethyl or Ferrocenylmethyl Group as R1-Substituent
2.4. In Vitro Cytotoxicity Study of the Reference and Novel Impiridones
3. Materials and Methods
3.1. General Procedure for the Synthesis of Impiridones Type 7
3.1.1. Synthesis of 2-(Methylthio)-4,5-Dihydro-1H-imidazole-1-carboxylate (5)
3.1.2. Synthesis of N-Aralkyl-4,5-dihydro-1H-imidazol-2-amine as Representative Example for the Preparation of the Cyclic Guanidines 6b–j
3.1.3. General Procedure for the Synthesis of Impiridones Type 7
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds of type 7 are available from the authors. |
Short-Term Treatment a | Long-Term Treatment b | |||||||
---|---|---|---|---|---|---|---|---|
R1 | R2 | HT-29 | A-2058 | A-2058 | PANC-1 | COLO-205 | EBC-1 | |
7ab | 16.9 ± 8.6 | 27.6 ± 2.5 | >25 | 1.7 ± 0.3 | 5.0 ± 2.9 | 7.0 ± 0.5 | ||
7ac | 43.3 ± 38.6 | 35.1 ± 30.6 | >25 | 0.16 ± 0.03 | 0.25 ± 0.03 | 25.0 ± 2.1 | ||
7ad | - | - | >10 | >10 | >10 | >10 | ||
7ae | 58.6 ± 18.6 | - | >10 | >25 | >10 | >10 | ||
7af | 55.7 ± 3.8 | 45.4 ± 2.6 | 37.9 ± 15.3 | 36.6 ± 3.4 | 33.1 ± 6.8 | 28.9 ± 6.8 | ||
7ag | - | - | 12.9 ± 1.6 | >25 | 12.8 ± 1.7 | ~25 ± 5.9 | ||
7ah | 2.7 ± 1.1 | 8.8 ± 7.1 | >25 | 0.3 ± 0.1 | 0.21 ± 0.05 | 1.0 ± 0.1 | ||
7ai | 14.3 ± 7.8 | 14.2 ± 8.1 | >25 | 0.28 ± 0.06 | ~0.25 ± 0.03 | ~25.0 ± 1.9 | ||
7aj | 69.4 ± 7.8 | >100 | > 50 | ~50 ± 13.9 | 17.8 ± 1.0 | >50 | ||
7db | >100 | >100 | >10 | >25 | >10 | >10 | ||
7eb | >100 | >100 | >25 | >25 | >25 | >25 | ||
7fb | 72.4 ± 13.0 | 52.0 ± 1.1 | 15.9 ± 1.8 | 38.0 ± 3.1 | 16.7 ± 3.0 | 24.3 ± 2.3 | ||
7gb | 26.5 ± 15.2 | 36.3 ± 13.4 | 11.8 ± 0.7 | >25 | 11.4 ± 0.1 | 15.7 ± 3.4 | ||
7hb | >100 | 12.8 ± 0.2 | >50 | 21.6 ± 2.2 | 32.0 ± 1.4 | 18.0 ± 2.5 | ||
7dc | 40.9 ± 2.4 | 28.1 ± 13.3 | 7.7 ± 1.2 | 21.4 ± 2.6 | 5.7 ± 0.9 | 8.0 ± 1.5 | ||
7dd | 35.6 ± 0.5 | 31.2 ± 8.9 | 5.8 ± 0.7 | >25.0 | 5.0 ± 3.1 | >10 | ||
7de | 33.0 ± 23.3 | 20.9 ± 12.5 | 3.3 ± 0.3 | 16.3 ± 0.2 | 2.7 ± 0.1 | 11.1 ± 0.3 | ||
7dh | >100 | 57.2 ± 20.2 | 8.0 ± 0.7 | 36.8 ± 2.5 | 13.5 ± 1.0 | 15.7 ± 0.6 | ||
7dj | >100 | 42.0 ± 26.8 | 11.8 ± 0.4 | >50 | 13.0 ± 3.2 | 17.1 ± 1.1 | ||
7ed | 11.6 ± 3.5 | 13.5 ± 8.5 | 11.2 ± 5.6 | >25 | 9.4 ± 1.6 | 13.1 ± 2.4 | ||
7ee | 34.0 ± 9.9 | 17.6 ± 6.7 | 12.1 ± 4.9 | >25 | 8.5 ± 0.9 | >25 | ||
7gc | 40.2 ± 5.3 | 28.7 ± 11.9 | 13.1 ± 0.9 | 22.2 ± 2.9 | 7.7 ± 2.2 | 12.8 ± 1.8 | ||
7gh | >100 | 49.8 ± 13.6 | 22.9 ± 2.5 | >50 | 29.2 ± 2.3 | 28.2 ± 1.4 | ||
7gi | 39.9 ± 9.8 | 32.3 ± 12.5 | 17.0 ± 1.3 | 19.9 ± 0.6 | 20.6 ± 0.6 | 18.3 ± 0.3 | ||
7hh | 8.3 ± 0.8 | - | 31.6 ± 4.6 | 4.1 ± 0.2 | 2.3 ± 0.5 | 9.4 ± 3.8 |
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Share and Cite
Bárány, P.; Oláh, R.S.; Kovács, I.; Czuczi, T.; Szabó, C.L.; Takács, A.; Lajkó, E.; Láng, O.; Kőhidai, L.; Schlosser, G.; et al. Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships. Molecules 2018, 23, 2248. https://doi.org/10.3390/molecules23092248
Bárány P, Oláh RS, Kovács I, Czuczi T, Szabó CL, Takács A, Lajkó E, Láng O, Kőhidai L, Schlosser G, et al. Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships. Molecules. 2018; 23(9):2248. https://doi.org/10.3390/molecules23092248
Chicago/Turabian StyleBárány, Péter, Rita Szabó Oláh, Imre Kovács, Tamás Czuczi, Csenge Lilla Szabó, Angéla Takács, Eszter Lajkó, Orsolya Láng, László Kőhidai, Gitta Schlosser, and et al. 2018. "Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships" Molecules 23, no. 9: 2248. https://doi.org/10.3390/molecules23092248