In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. AR and PTP1B Inhibition
2.3. Kinetic Studies
2.4. AR and PTP1B Docking Experiments
2.5. Ex Vivo Assays
3. Materials and Methods
3.1. Chemistry
3.1.1. General Procedure for the Synthesis of 5-arylidene-2,4-dioxothiazolidinones 6a–i
3.1.2. General Procedure for the Synthesis of 3-(5-arylidene-2,4-dioxothiazolidin-3-yl)propanoic Acids 3a–f
3.1.3. General Procedure for the Synthesis of 3-(5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)propanoic Acids 4a–f
3.1.4. General Procedure for the Synthesis of 4-(5-arylidene-2,4-dioxothiazolidin-3-yl)-2-butenoic Acids 5a–e
3.2. Enzymatic Assays
3.2.1. AR Enzymatic Assay, Expression and Purification
3.2.2. Inhibition Studies on AR
3.2.3. Enzymatic Assays with PTP1B
3.2.4. Reversibility Assay (Dilution Test) with PTP1B
3.2.5. Evaluation of Action Mechanism of Inhibitors
3.3. Ex Vivo Assay
3.3.1. Cell Cultures
3.3.2. Cell Viability Assay
3.3.3. Evaluation of Insulin Mimetic/Sensibilizing Activity of Inhibitors
3.4. Molecular Docking
Virtual Screening
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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X | R | Ar | AR IC50 (µM) | PTP1B IC50 (µM) | |
---|---|---|---|---|---|
3a | O | (CH2)2COOH | 3-OC6H5-C6H4 | 11.9 ± 0.9 | 79% at 50 µM |
3b | O | (CH2)2COOH | 4-OC6H5-C6H4 | 43.8 ± 7.1 | 56% at 50 µM |
3c | O | (CH2)2COOH | 3-OCH2C6H5-C6H4 | 14.3 ± 1.0 | 76% at 50 µM |
3d | O | (CH2)2COOH | 4-OCH2C6H5-C6H4 | 35.7 ± 3.0 | 77% at 50 µM |
3e | O | (CH2)2COOH | 3-OCH2CH2C6H5-C6H4 | 27.9 ± 3.1 | 64% at 50 µM |
3f | O | (CH2)2COOH | 4-OCH2CH2C6H5-C6H4 | 50.2 ± 4.6 | 46% at 50 µM |
4a | S | (CH2)2COOH | 3-OC6H5-C6H4 | 2.2 ± 0.1 | 34.1 ± 0.5 |
4b | S | (CH2)2COOH | 4-OC6H5-C6H4 | 7.6 ± 0.6 | 29.5 ± 0.4 |
4c | S | (CH2)2COOH | 3-OCH2C6H5-C6H4 | 3.8 ± 0.1 | 42.8 ± 0.7 |
4d | S | (CH2)2COOH | 4-OCH2C6H5-C6H4 | 8.4 ± 0.7 | 34.9 ± 0.7 |
4e | S | (CH2)2COOH | 3-OCH2CH2C6H5-C6H4 | 2.3 ± 0.1 | 55.5 ± 0.8 |
4f | S | (CH2)2COOH | 4-OCH2CH2C6H5-C6H4 | 5.3 ± 0.4 | 12.7 ± 0.3 |
5a | O | CH2CH=CHCOOH | 3-OC6H5-C6H4 | 3.9 ± 0.2 | 42.1 ± 0.3 |
5b | O | CH2CH=CHCOOH | 4-OC6H5-C6H4 | 84% at 10 µM | 39.7 ± 0.1 |
5c | O | CH2CH=CHCOOH | 4-C6H5-C6H4 | 88% at 5 µM | 34.8 ± 0.5 |
5d | O | CH2CH=CHCOOH | 1-naphthyl | 3.7 ± 0.2 | 40.3 ± 0.5 |
5e | O | CH2CH=CHCOOH | 2-naphthyl | 86% at 10 µM | 37.1 ± 0.4 |
Epalrestat | 0.102 ± 0.005 | ||||
Vanadate | 0.4 ± 0.01 |
AR | PTP1B | |||
---|---|---|---|---|
Inhibitor | Ki (µM) | K′i (µM) | Ki (µM) | K′i (µM) |
4a | 5.0 ± 0.57 | 1.4 ± 0.022 | 10.6 ± 1.7 | 68.9 ± 1.5 |
4e | >8 | 0.66 ± 0.30 | 2.2 ± 0.3 | >12 |
4f | >30 | 2.9 ± 0.12 | 0.9 ± 0.1 | 2.3 ± 0.1 |
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Ottanà, R.; Paoli, P.; Cappiello, M.; Nguyen, T.N.; Adornato, I.; Del Corso, A.; Genovese, M.; Nesi, I.; Moschini, R.; Naß, A.; et al. In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B. Molecules 2021, 26, 330. https://doi.org/10.3390/molecules26020330
Ottanà R, Paoli P, Cappiello M, Nguyen TN, Adornato I, Del Corso A, Genovese M, Nesi I, Moschini R, Naß A, et al. In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B. Molecules. 2021; 26(2):330. https://doi.org/10.3390/molecules26020330
Chicago/Turabian StyleOttanà, Rosaria, Paolo Paoli, Mario Cappiello, Trung Ngoc Nguyen, Ilenia Adornato, Antonella Del Corso, Massimo Genovese, Ilaria Nesi, Roberta Moschini, Alexandra Naß, and et al. 2021. "In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B" Molecules 26, no. 2: 330. https://doi.org/10.3390/molecules26020330