Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Computational Analysis
2.3. Biological Evaluations
2.3.1. Antiproliferative Evaluations
2.3.2. Apoptosis Detection
3. Materials and Methods
3.1. General
3.2. Experimental Procedure for the Synthesis of Compounds
3.3. General Procedure for the N-Alkylation of Compounds
3.4. General Procedure for the Synthesis of Azidoethyl Derivatives
3.5. General Procedure for the Synthesis of bis- (5a–5d, 9a–9d, 10a–10d, 11a, 11d) and Mono- (5f, 5g, 9e–9g, 10f, 11e, 11g, 11h) Pyrrolo[2,3-d]pyrimidines and Purines
3.6. General Procedure for the Synthesis of Bis-Pyrrolo[2,3-d]pyrimidine Derivatives 6a–6d and 7a–7d
3.7. Computational Details
3.8. Cell Culturing
3.9. Proliferation Assay
3.10. Apoptosis Detection
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Base | X | Compd | Yield (%) | ||
---|---|---|---|---|---|
Method A 1 | Method B 2 | Method C 3 | |||
| | 5a | 49 | 67 | 24 |
- | - | - | - | ||
| 5b | 34 | 66 | 35 | |
5f | - | - | 14 | ||
CH2CH2CH2 | 5c | 45 | 62 | 63 | |
5g | 11 | - | 35 | ||
CH2OCH2 | 5d | 51 | − 4 | 64 | |
- | - | − 4 | - | ||
| | 9a | 28 | 61 | 36 |
9e | 4 | - | 29 | ||
| 9b | 48 | 69 | 38 | |
9f | - | - | 31 | ||
CH2CH2CH2 | 9c | 40 | 62 | 21 | |
8g | - | - | 10 | ||
CH2OCH2 | 9d | 55 | −4 | 46 | |
- | - | −4 | - | ||
| | 10a | 28 | 61 | 60 |
- | - | - | - | ||
| 10b | 60 | 80 | 49 | |
10f | - | - | 61 | ||
CH2CH2CH2 | 10c | 50 | 82 | 58 | |
- | - | - | - | ||
CH2OCH2 | 10d | 48 | −4 | 58 | |
- | - | −4 | - | ||
| | 11a | - | 11 | - |
11e | - | - | 25 | ||
| - | - | - | - | |
- | - | - | - | ||
CH2CH2CH2 | - | - | - | - | |
11g | - | - | 55 | ||
CH2OCH2 | 11d | - | −4 | 8 | |
11h | - | −4 | 7 |
| | |||||
---|---|---|---|---|---|---|
Base | X | Compd | IC50 1 (µM) | |||
A549 | HeLa | CFPAC-1 | SW620 | |||
| | BIS-PP1 | 9.4 ± 1.16 | 7.0 ± 0.64 | 3.6 ± 2.02 | 40.8 ± 3.83 |
| BIS-PP2 2 | 4.2 ± 1.39 | 2.3 ± 0.99 | 0.95 ± 0.28 | 6.8 ± 0.69 | |
| 5a | >100 | 77.0 ± 2.6 | >100 | >100 | |
| 5b 2 | 6.3 ± 1.2 | >100 | >100 | >100 | |
5f 2 | 6.9 ± 1.1 | 0.98 ± 0.44 | 0.79 ± 0.03 | 8.0 ± 1.8 | ||
CH2 | 5c | 99.6 ± 1.5 | 99.7 ± 5.9 | 74.9 ± 3.8 | >100 | |
5g | >100 | 75.0 ± 3.5 | 19.5 ± 4.0 | 80.5 ± 14.9 | ||
O | 5d | >100 | >100 | 36.5 ± 3.9 | 53.5 ± 4.8 | |
| | 6a | >100 | >100 | >100 | >100 |
| 6b | 53.9 ± 2.1 | 68.5 ± 3.2 | 17.4 ± 6.3 | 24.7 ± 8.7 | |
CH2 | 6c | 59.3 ± 4.9 | 33.7 ± 8.9 | 48.7 ± 1.5 | 65.2 ± 4.8 | |
O | 6d | 51.9 ± 3.0 | 28.2 ± 9.0 | 37.9 ± 3.7 | 45.5 ± 3.3 | |
| | 7a 2 | 49.3 ± 6.4 | 6.4 ± 0.35 | 25.8 ± 0.98 | 78.0 ± 2.1 |
| 7b | 69.0 ± 1.2 | 54.6 ± 5.2 | 77.4 ± 3.5 | >100 | |
CH2 | 7c | >100 | 80.0 ± 1.5 | 65.3 ± 5.7 | >100 | |
O | 7d | >100 | >100 | >100 | >100 | |
| | 9a 2 | 53.5 ± 8.0 | 16.2 ± 0.05 | 9.1 ± 1.3 | 43.5 ± 4.4 |
9e | 58.7 ± 10.2 | 17.1 ± 1.3 | 23.4 ± 4.2 | 35.7 ± 0.79 | ||
| 9b2 | 12.3 ± 3.4 | 3.8 ± 0.81 | 8.1 ± 1.3 | 5.2 ± 2.2 | |
9f2 | 9.3 ± 0.1 | 3.9 ± 0.69 | 2.9 ± 1.0 | 23.2 ± 3.2 | ||
CH2 | 9c | >100 | 41.2 ± 0.99 | 53.9 ± 3.4 | >100 | |
9g | >100 | 72.2 ± 9.0 | 75.2 ± 12.2 | >100 | ||
O | 9d | 73.1 ± 7.7 | 34.7 ± 12.1 | 56.8 ± 2.9 | 66.1 ± 3.0 | |
| | 10a | 95.0 ± 3.2 | 60.6 ± 5.9 | 48.5 ± 1.6 | 98.3 ± 7.4 |
| 10b 2 | 8.5 ± 0.1 | 7.4 ± 0.09 | 16.4 ± 4.6 | 59.1 ± 0.34 | |
10f 2 | 62.1 ± 2.3 | 8.1 ± 2.2 | 6.5 ± 0.78 | 98.0 ± 1.3 | ||
CH2 | 10c | 88.6 ± 6.4 | 60.4 ± 5.0 | 49.9 ± 1.7 | >100 | |
O | 10d | 87.3 ± 4.4 | 66.9 ± 11.2 | 52.5 ± 4.6 | 63.4 ± 3.6 | |
| | 11a | >100 | >100 | >100 | >100 |
11e | >100 | >100 | >100 | >100 | ||
CH2 | 11g | >100 | >100 | >100 | >100 | |
O | 11d | >100 | >100 | >100 | >100 | |
11h | >100 | >100 | >100 | >100 |
48 h Treatment | 72 h Treatment | |||||
---|---|---|---|---|---|---|
CFPAC-1 | Control (%) | 5f (%) 1.85 µM | 5f (%) 3.95 µM | Control (%) | 5f (%) 1.85 µM | 5f (%) 3.95 µM |
viable cells | 96.58 ± 0.54 | 79.64 ± 2.57 | 68.18 ± 0.94 | 90.48 ± 0.02 | 56.25 ± 6.56 | 27.93 ± 3.23 |
early apoptotic cells | 0.0 | 11.76 ± 3.58 | 21.21 ± 1.35 | 6.28 ± 1.53 | 30.36 ± 1.49 | 39.63 ± 8.54 |
late apoptotic/primary necrotic cells | 0.86 ± 0.05 | 5.88 ± 1.44 | 6.56 ± 0.24 | 0.0 | 10.71 ± 4.89 | 26.14 ± 2.57 |
secondary necrotic cells | 2.56 ± 1.40 | 2.72 ± 0.56 | 4.05 ± 1.22 | 3.24 ± 0.92 | 2.68 ± 0.37 | 6.3 ± 2.45 |
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Bistrović Popov, A.; Vianelo, R.; Grbčić, P.; Sedić, M.; Pavelić, S.K.; Pavelić, K.; Raić-Malić, S. Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation. Molecules 2021, 26, 3334. https://doi.org/10.3390/molecules26113334
Bistrović Popov A, Vianelo R, Grbčić P, Sedić M, Pavelić SK, Pavelić K, Raić-Malić S. Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation. Molecules. 2021; 26(11):3334. https://doi.org/10.3390/molecules26113334
Chicago/Turabian StyleBistrović Popov, Andrea, Robert Vianelo, Petra Grbčić, Mirela Sedić, Sandra Kraljević Pavelić, Krešimir Pavelić, and Silvana Raić-Malić. 2021. "Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation" Molecules 26, no. 11: 3334. https://doi.org/10.3390/molecules26113334
APA StyleBistrović Popov, A., Vianelo, R., Grbčić, P., Sedić, M., Pavelić, S. K., Pavelić, K., & Raić-Malić, S. (2021). Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation. Molecules, 26(11), 3334. https://doi.org/10.3390/molecules26113334