Tetrasubstituted Pyrrole Derivative Mimetics of Protein–Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells
Abstract
:1. Introduction
2. Results and Discussion
2.1. Design and Synthesis of the New TSP Derivatives
2.2. Solubility Assay
2.3. Biological Evaluation
2.4. Apoptosis Studies
2.5. Computational Studies
2.5.1. Conformational Analysis
2.5.2. Investigation of the Peptidomimetic Ability of the New TSPs
2.6. SAR Analysis
3. Materials and Methods
3.1. Chemistry
3.2. Cell Cultures
3.3. Bioscreens In Vitro for Anticancer Activity
3.4. Apoptosis/Necrosis Detection
3.5. Statistical Analysis
3.6. Solubility Assay
3.7. Molecular Modeling Studies
3.7.1. Conformational Analysis
3.7.2. Structural and Bioinformatics Studies
4. Conclusions
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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Cpd | W | R1 | R2 | R3 |
1 | C=O | CH3 | 3-Cl | H |
9a | C=O | Cl | 3-Cl | H |
9b | C=O | OCH3 | 3-Cl | H |
9c | C=O | F | 3-Cl | H |
9d | C=O | CH3 | 4-Cl | H |
9e | C=O | Cl | 4-Cl | H |
9f | C=O | H | 3-CF3 | H |
9h | C=O | CH3 | 3-Cl | CH3 |
9i | C=O | CH3 | 3-Cl | OCH3 |
10a | C=O | NH2 | 3-Cl | H |
(±)10b | CHOH | CH3 | 3-Cl | H |
Cpd | Solubility a (µM) |
---|---|
1 | 3.5 ± 0.1 |
9a | 3.9 ± 0.1 |
9b | 3.1 ± 0.2 |
9c | 3.9 ± 0.2 |
9d | 3.1 ± 0.2 |
9e | 3.5 ± 0.3 |
9f | 2.6 ± 0.1 |
9g | 1.5 ± 0.2 |
9h | <1.0 |
9i | <1.0 |
10a | 10.5 ± 0.1 |
(±)10b | 6.7 ± 0.6 |
nutlin-3a | 2.4 ± 0.2 |
Cpd | A375 a IC50 (µM) b | L6 c IC50 (µM) b | SI d | HCT-116 e IC50 (µM) b |
---|---|---|---|---|
1 | 20 ± 4 | 42 ± 3 | 2.1 | 41.4 ± 6 |
9a | 18 ± 4 | 48 ± 5 | 2.7 | 36.4 ± 8 |
9b | 24 ± 14 | 40 ± 5 | 1.7 | 46 ± 18 |
9c | 13 ± 4 | 35 ± 4 | 2.7 | 55.9 ± 7 |
9d | 15 ± 5 | 25 ± 6 | 1.7 | 35.4 ± 6 |
9e | 23 ± 6 | 38 ± 2 | 1.6 | 34.6 ± 6 |
9f | 27 ± 8 | 35 ± 7 | 1.3 | 28.4 ± 7 |
9g | 18 ± 5 | 71 ± 5 | 3.9 | 34 ± 6 |
9h | 24 ± 6 | 42 ± 7 | 1.7 | 56.3 ± 15 |
9i | 16 ± 6 | 66 ± 5 | 4.2 | 167.6 ± 9 |
10a | 10 ± 4 | 55 ± 7 | 5.6 | 41.3 ± 6 |
(±)10b | 15 ± 5 | 54 ± 6 | 3.6 | 25 ± 5 |
nutlin-3a | 15 ± 3 | 18 ± 4 | 1.2 | 12.5 ± 5 |
Family a | Sub-Family | ΔEGM (kcal/mol) | Distances (Å) | Torsional Angles (°) b–f | ||||||
d1 (X-Y) | d2 (X-Z) | d3 (Y-Z) | τ1 | τ2 | τ3 | τ4 | τ5 | |||
TCC | I | 0.00 | 6.4 | 8.7 | 9.3 | −174 | 26 | −21 | 77 | −112 |
TCC | II | 0.49 | 5.6 | 9.3 | 10.2 | −174 | 28 | 22 | 75 | −82 |
TCT | I | 1.57 | 7.4 | 7.2 | 11.0 | −174 | 27 | −148 | 102 | −111 |
TCT | III | 1.65 | 9.7 | 7.2 | 10.7 | −173 | 27 | −148 | 101 | 123 |
Pharmacophore | TSP Ring | PPI Motif | |||
---|---|---|---|---|---|
23VxxLxxxV30 | 14LxxxLxxL21 | ||||
Hot-Spot Residues a | |||||
X | i + 3 | i + 3 | i + 4 | i + 4 | |
1 | Y | i | i + 7 | i | i + 7 |
Z | i + 7 | i | i + 7 | i | |
X | i + 3 | i + 3 | i + 4 | i + 4 | |
2 | Y | i | i + 7 | i | i + 7 |
Z | i + 7 | i | i + 7 | i | |
X | i + 3 | i + 3 | i + 4 | i + 4 | |
3 | Y | i | i + 7 | i | i + 7 |
Z | i + 7 | i | i + 7 | i | |
X | i | i + 7 | i | i + 7 | |
4 | Y | i + 7 | i | i + 7 | i |
Z | i + 3 | i + 3 | i + 4 | i + 4 |
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Persico, M.; Galatello, P.; Ferraro, M.G.; Irace, C.; Piccolo, M.; Abduvakhidov, A.; Tkachuk, O.; d’Aulisio Garigliota, M.L.; Campiglia, P.; Iannece, P.; et al. Tetrasubstituted Pyrrole Derivative Mimetics of Protein–Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells. Molecules 2023, 28, 4161. https://doi.org/10.3390/molecules28104161
Persico M, Galatello P, Ferraro MG, Irace C, Piccolo M, Abduvakhidov A, Tkachuk O, d’Aulisio Garigliota ML, Campiglia P, Iannece P, et al. Tetrasubstituted Pyrrole Derivative Mimetics of Protein–Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells. Molecules. 2023; 28(10):4161. https://doi.org/10.3390/molecules28104161
Chicago/Turabian StylePersico, Marco, Paola Galatello, Maria Grazia Ferraro, Carlo Irace, Marialuisa Piccolo, Avazbek Abduvakhidov, Oleh Tkachuk, Maria Luisa d’Aulisio Garigliota, Pietro Campiglia, Patrizia Iannece, and et al. 2023. "Tetrasubstituted Pyrrole Derivative Mimetics of Protein–Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells" Molecules 28, no. 10: 4161. https://doi.org/10.3390/molecules28104161