Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Assays
2.3. Molecular Modeling
2.4. Chemical Space
3. Materials and Methods
3.1. Chemistry
- Synthesis of 2-(adamantane-1-carbonyl)hydrazine-1-carbothioamide 15
- Synthesis of 5-(adamantan-1-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 16
- General procedure for obtaining 1,2,4-triazole derivatives 20a–20g
- 5-(Adamantan-1-yl)-3-((3,7-dimethyloctyl)thio)-1H-1,2,4-triazole 20a
- 5-(Adamantan-1-yl)-3-(((S)-3,7-dimethyloct-6-en-1-yl)thio)-1H-1,2,4-triazole 20b
- 5-(Adamantan-1-yl)-3-(((E)-3,7-dimethylocta-2,6-dien-1-yl)thio)-1H-1,2,4-triazole 20c
- 5-(Adamantan-1-yl)-3-(((Z)-3,7-dimethylocta-2,6-dien-1-yl)thio)-1H-1,2,4-triazole 20d
- 5-(Adamantan-1-yl)-3-((((S)-4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl)thio)-1H-1,2,4-triazole 20e
- 5-(Adamantan-1-yl)-3-((((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)thio)-1H-1,2,4-triazole 20f
- 5-(Adamantan-1-yl)-3-((2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl)thio)-1H-1,2,4-triazole 20g
- General procedure for synthesis of bromides
- Synthesis of 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine 17
- Synthesis of 3,7-dimethyloctanoic acid 23a
- Synthesis of (-)-myrtenic acid 23c
- Synthesis of (S)-4-(prop-1-en-2-yl)cyclohex-1-ene-1-carboxylic acid 23d
- General procedure for acid chloride synthesis
- General procedure for obtaining 25a–d and 26a
- N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-3,7-dimethyloctanamide 25a
- N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-3,7-dimethyloct-6-enamide 25b
- (1R,5S)-N-(5-(Adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carboxamide 25c
- (S)-N-(5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl)-4-(prop-1-en-2-yl)cyclohex-1-ene-1-carboxamide 25d
- N-(Adamantan-1-yl)-3,7-dimethyloctanamide 26a
3.2. Biology
3.2.1. Detection of Tdp1 Activity
3.2.2. Cytotoxicity Assays
3.3. Molecular Modeling and Screening
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
Abbreviations
Tdp1 | Tyrosyl-DNA phosphodiesterase 1 |
DMSO | Dimethyl sulfoxide |
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Structure | IC50, μM | CC50, μM HeLa | CC50, μM HCT-116 | CC50, μM SW837 | |
---|---|---|---|---|---|
1,2,4-Triazole derivatives | |||||
20a | | 0.54 ± 0.09 | 85 ± 23 | 27 ± 6 | 52 ± 6 |
20b | | 1.5 ± 0.3 | >100 | >100 | 41 ± 4 |
20c | | 5.3 ± 1.7 | 64 ± 6 | 16 ± 7 | 41 ± 6 |
20d | | 5.6 ± 0.6 | 31± 11 | 20 ± 9 | 17 ± 5 |
20e | | 6.2 ± 2.2 | 24 ± 16 | 15 ± 5 | 40 ± 4 |
20f | | 7.5 ± 1.8 | 15 ± 2 | 54 ± 5 | 46 ± 6 |
20g | | 0.57 ± 0.14 | 74 ± 17 | 34 ± 6 | 40 ± 4 |
1,3,4-Thiadiazole derivatives | |||||
25a | | 0.35 ± 0.05 | >100 | >100 | >100 |
25b | | 2.59 ± 0.48 | >100 | 66 ± 6 | 83 ± 8 |
25c | | 0.45 ± 0.09 | >100 | >100 | >100 |
Compound | HeLa—CC50, μM | HCT116—CC50, nM |
---|---|---|
Topotecan | 6.0 | 715.0 |
20a | 4.5 | 650.0 (20) |
20b | ND * | 575.3 (20) |
20c | 1.9 | 460.0 (15) |
20d | 5.4 | 689.0 (15) |
20e | ND | 392.0 (15) |
20f | 2.8 | 715.0 (25) |
20g | 2.6 | 235.8 (20) |
25a | 4.9 | 455.7 (45) |
25b | 2.9 | 611.9 (20) |
25c | 3.6 | 486.0 (25) |
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Munkuev, A.A.; Mozhaitsev, E.S.; Chepanova, A.A.; Suslov, E.V.; Korchagina, D.V.; Zakharova, O.D.; Ilina, E.S.; Dyrkheeva, N.S.; Zakharenko, A.L.; Reynisson, J.; et al. Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments. Molecules 2021, 26, 3128. https://doi.org/10.3390/molecules26113128
Munkuev AA, Mozhaitsev ES, Chepanova AA, Suslov EV, Korchagina DV, Zakharova OD, Ilina ES, Dyrkheeva NS, Zakharenko AL, Reynisson J, et al. Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments. Molecules. 2021; 26(11):3128. https://doi.org/10.3390/molecules26113128
Chicago/Turabian StyleMunkuev, Aldar A., Evgenii S. Mozhaitsev, Arina A. Chepanova, Evgeniy V. Suslov, Dina V. Korchagina, Olga D. Zakharova, Ekaterina S. Ilina, Nadezhda S. Dyrkheeva, Alexandra L. Zakharenko, Jóhannes Reynisson, and et al. 2021. "Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments" Molecules 26, no. 11: 3128. https://doi.org/10.3390/molecules26113128