Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies
Abstract
:1. Introduction
2. Chemistry
3. Biochemical Assays and SAR Analysis
3.1. CA Inhibition Results
- Due to the complete lack of activity towards hCA I and II showing a Ki ˃ 10,000 nM, the test compounds fulfill the primary goal of selectivity towards membrane-anchored hCAs vs. the cytosolic enzymes;
- All molecules, apart from 1 and 11, present the structural requisites that are compatible with a potent (one-/two-digit nanomolar Ki values) hCA XII inhibition;
- hCA IX inhibitory activity is maintained in the low nanomolar range for the smaller amino acyl-coumarin series (compounds 1, 2, 6–8), whereas the extension of the (pseudo)-peptidyl chain results in up to an eleven-fold reduction of Ki values when compared to the most effective inhibitor 6 (excluding compounds 18 and 20, which is similar in potency to 2 and 7, respectively);
- In the amino acyl coumarin series, hCA inhibitory potency decreases from compounds with small N-protecting groups to analogs bearing more extended and lipophilic moieties;
- The general inhibitory profile discloses a significant selectivity towards hCA XII compared to the other isoform that is relevant to cancer; the most remarkable SI values are found in the (pseudo)-dipeptidyl coumarin series of derivatives (except 20), which all share the urea structural motif;
- The replacement of AMC for AMMC in similar structures (pairs 6/7 and 17/20) gives rise to unexpected effects, with a slight reduction of activity against both isoforms for the amino acyl-coumarin derivatives, whereas for the (pseudo)-dipeptidyl coumarin analogs the same replacement was found to cause a six-fold increase in hCA IX inhibition and a similar reduction in inhibitory activity towards hCA XII;
- The external amino acid also affects activity as observed with the (pseudo)-dipeptidyl AMC conjugates. The inhibition potency towards CA IX increases in the order βAla, Gly, Ala, and Phe, suggesting that, in the active site, a larger space is available for additional hydrophobic interactions involving the side chain; Ala and βAla, on the other hand, are the preferred residues for potent hCA XII inhibitory activity, which may be explained by suitable conformational rearrangements into the isoform binding site.
3.2. MAO Inhibition Results
3.3. Computational Studies
4. Conclusions
5. Experimental Section
5.1. Chemical Synthesis
5.1.1. General Procedure for the Synthesis of Z/Fmoc-Xaa-AMC/AMMC Derivatives (1–3, 8, and 9)
5.1.2. General Protocol for the N-Deprotection of Fmoc-Xaa-AMC/AMMC Derivatives (2, 3, 9): Preparation of 4, 5, and 10
5.1.3. General Procedure for the Synthesis of Ac-Ala-AMC/AMMC (6 and 7)
5.1.4. Synthesis of Z-Ala-tLeu-AMMC (11)
5.1.5. General Protocol for the Preparation of Active Carbamates (12–15)
5.1.6. General Procedure for the Synthesis of (Pseudo)-Dipeptidyl Coumarins (16–20)
5.2. Biological Methods
5.2.1. hCA Inhibition Assay
5.2.2. hMAO Inhibition Studies
5.3. Computational Studies
5.3.1. Ligand Preparation
5.3.2. hCA Structure Preparation and Docking
5.3.3. Molecular Dynamics of the CA XII:Ligand 19 Complex
5.3.4. hMAO-A and hMAO-B Protein Structure Preparation and Docking
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Compound | Ki hCA I | Ki hCA II | Ki hCA IX | Ki hCA XII | SI hCA IX over hCA I or hCA II b | SI hCA XII over hCA I or hCA II b | SI hCA XII over hCA IX c |
---|---|---|---|---|---|---|---|
Z-Ala-AMC (1) | >10,000 | >10,000 | 30.5 | 110.0 d | >327.9 | >90.9 | 0.3 |
Fmoc-Ala-AMC (2) | >10,000 | >10,000 | 91.0 | 37.2 | >109.9 | >268.8 | 2.4 |
Ac-Ala-AMC (6) | >10,000 | >10,000 | 23.4 | 30.5 | >427.3 | >327.9 | 0.8 |
Ac-Ala-AMMC (7) | >10,000 | >10,000 | 29.4 | 46.8 | >340.1 | >213.7 | 0.6 |
Z-Ile-AMMC (8) | >10,000 | >10,000 | 78.7 | 41.5 | >127.1 | >241.0 | 1.9 |
Z-Ala-tLeu-AMMC (11) | >10,000 | >10,000 | 171.5 | 336.3 | >58.3 | >29.7 | 0.5 |
MeO-Gly-CO-Ala-AMC (16) | >10,000 | >10,000 | 183.3 | 38.2 | >54.6 | >261.8 | 4.8 |
MeO-Ala-CO-Ala-AMC (17) | >10,000 | >10,000 | 163.3 | 9.6 | >61.2 | >1041.7 | 17.0 |
MeO-Phe-CO-Ala-AMC (18) | >10,000 | >10,000 | 93.6 | 40.0 | >106.8 | >250.0 | 2.3 |
EtO-βAla-CO-Ala-AMC (19) | >10,000 | >10,000 | 260.5 | 9.5 | >38.4 | >1052.6 | 27.4 |
MeO-Ala-CO-Ala-AMMC (20) | >10,000 | >10,000 | 27.0 | 54.7 | >370.4 | >182.8 | 0.5 |
AAZ | 250.0 | 12.1 | 25.8 | 5.7 | 9.7 0.5 | 43.8 2.1 | 4.5 |
Compound | MAO-A (IC50 μM) | MAO-B (IC50 μM) |
---|---|---|
Z-Ala-MAC (1) | 9.31 ± 0.132 | >100 |
Fmoc-Ala-MAC (2) | 54.8 ± 0.028 | >100 |
Ac-Ala-MAC (6) | 1.92 ± 0.247 | >100 |
Ac-Ala-MMAC (7) | 12.0 ± 0.693 | 45.6 ± 1.85 |
Z-Ile-MMAC (8) | 47.0 ± 13.5 | >100 |
Z-Ala-tLeu-MMAC (11) | 41.3 ± 17.8 | 79.5 ± 7.24 |
MeO-Gly-CO-Ala-MAC (16) | 5.910 ± 0.155 | >100 |
MeO-Ala-CO-Ala-MAC (17) | 69.6 ± 9.28 | 58.6 ± 24.0 |
MeO-Phe-CO-Ala-MAC (18) | 21.8 ± 0.092 | 78.0 ± 22.3 |
EtO-βAla-CO-Ala-MAC (19) | >100 | >100 |
MeO-Ala-CO-Ala-MMAC (20) | >100 | 75.3 ± 0.976 |
Harmine | 0.0041 ± 0.00007 | - |
Isatin | 8.43 ± 0.245 | 3.90 ± 0.792 |
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Agamennone, M.; Fantacuzzi, M.; Carradori, S.; Petzer, A.; Petzer, J.P.; Angeli, A.; Supuran, C.T.; Luisi, G. Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies. Molecules 2022, 27, 7884. https://doi.org/10.3390/molecules27227884
Agamennone M, Fantacuzzi M, Carradori S, Petzer A, Petzer JP, Angeli A, Supuran CT, Luisi G. Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies. Molecules. 2022; 27(22):7884. https://doi.org/10.3390/molecules27227884
Chicago/Turabian StyleAgamennone, Mariangela, Marialuigia Fantacuzzi, Simone Carradori, Anél Petzer, Jacobus P. Petzer, Andrea Angeli, Claudiu T. Supuran, and Grazia Luisi. 2022. "Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies" Molecules 27, no. 22: 7884. https://doi.org/10.3390/molecules27227884
APA StyleAgamennone, M., Fantacuzzi, M., Carradori, S., Petzer, A., Petzer, J. P., Angeli, A., Supuran, C. T., & Luisi, G. (2022). Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies. Molecules, 27(22), 7884. https://doi.org/10.3390/molecules27227884