Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Medicinal Chemistry
2.1.1. General
2.1.2. Synthesis of m-Nitro-Substituted Diphenylpyrazole 3a
Analytical Characterization
2.1.3. Synthesis of Anle138b-Based m-Anilino Derivative 1a
Analytical Characterization
2.1.4. Synthesis of Anle138b-Based m-Azido 2a
Analytical Characterization
2.1.5. Synthesis of Lenalidomide Alkynylamide Linker-CRBN Ligand Construct 4
Analytical Characterization
2.1.6. Synthesis of Anle138b m-Triazole Connected Lenalidomide PROTAC 8a
Analytical Characterization
2.2. Biological Studies
2.2.1. In Vitro Thioflavin T-Based Assay for αSyn Aggregation
2.2.2. Cytotoxic Effects of Anle138b-PROTAC Constructs on 4xSNCA iPSC-Derived Neurons
2.2.3. Cellular Assay for αSyn Aggregation on Patient-Derived DANs
3. Results
3.1. Medicinal Chemistry
3.1.1. Rational Design and Synthesis of m/p Anle138b-Based Analogues 2a,b Suitable for PROTAC Assembly
3.1.2. Synthesis of m/p Anle138b Analogues 1a,b, 2a,b for PROTAC Assembly
3.1.3. Synthesis of Thalidomide-/Lenalidomide-Linker Constructs 4–6 for Coupling with m/p Anle138b Analogues
3.1.4. PROTAC Hybrid Assembly: Click Reaction- and Amide-Based Strategies to 7a,b–9a,b
3.2. Biology Studies
3.2.1. In Vitro αSyn Aggregation Assay
3.2.2. Cellular Assay for αSyn Aggregation on Patient-Derived Dopaminergic Neurons
4. Discussion and Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Pedrini, M.; Iannielli, A.; Meneghelli, L.; Passarella, D.; Broccoli, V.; Seneci, P. Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation. Pharmaceutics 2023, 15, 1467. https://doi.org/10.3390/pharmaceutics15051467
Pedrini M, Iannielli A, Meneghelli L, Passarella D, Broccoli V, Seneci P. Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation. Pharmaceutics. 2023; 15(5):1467. https://doi.org/10.3390/pharmaceutics15051467
Chicago/Turabian StylePedrini, Martina, Angelo Iannielli, Lorenzo Meneghelli, Daniele Passarella, Vania Broccoli, and Pierfausto Seneci. 2023. "Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation" Pharmaceutics 15, no. 5: 1467. https://doi.org/10.3390/pharmaceutics15051467