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Development of Keap1-Nrf2 Protein-Protein Interaction inhibitors for the treatment of neurodegenerative diseases

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1. Introduction 1
1.1. Reactive Oxygen Species (ROS) & Oxidative Stress 1
1.2. Keap1-Nrf2-ARE pathway 3
1.3. Nrf2 as therapeutic target for chronic diseases 5
1.4. Keap1-Nrf2 Protein-Protein Interaction (PPI) Inhibitors 7
1.5. Fragment-Based Drug Discovery (FBDD) 10
2. Results and Discussion 13
2.1. Principle of assay 13
2.1.1. Fluorescence Polarization (FP) assay 13
2.1.2. Nrf2 Nuclear Translocation assay 15
2.2. Overview of previous studies 16
2.2.1. Fragment linking of selected fragments 16
2.2.2. Identification of Tetrahydroisoquinoline (THIQ) scaffold 17
2.3. Optimization of Lead compound 19
2.3.1. Synthesis scheme of Pyrazole intermediate 20
2.3.2. Design of compounds ①: 6,7-substituted THIQ compounds 21
2.3.2.1. Synthesis scheme of 6,7-substituted THIQ compounds 21
2.3.2.2. Biological evaluation of 6,7-substituted THIQ compounds 23
2.3.3. Design of compounds ②: 5,8-substituted THIQ compounds 25
2.3.3.1. Synthesis scheme of 5,8-substituted THIQ compounds 26
2.3.3.2. Biological evaluation of 5,8-substituted THIQ compounds 27
2.3.4. Modification of Benzylic position in THIQ compounds 29
2.3.5. Design of compounds ③: “Me” group in benzylic position + 6,7-substituted THIQ compounds 35
2.3.5.1. Synthesis scheme of “Me” group in benzylic position + 6,7-substituted THIQ compounds 35
2.3.5.2. Biological evaluation of “Me” group in benzylic position + 6,7-substituted THIQ compounds 38
2.3.6. Design of compounds ④: “m-Cl ph” group in benzylic position + 6,7-substituted THIQ compounds 40
2.3.6.1. Synthesis scheme of “m-Cl ph” group in benzylic position + 6,7-substituted THIQ compounds 40
2.3.6.2. Biological evaluation of “m-Cl ph” group in benzylic position + 6,7-substituted THIQ compounds 43
2.3.7. Design of compounds ⑤: “p-Cl ph” group in benzylic position + 6,7-substituted THIQ compounds 45
2.3.7.1. Synthesis scheme of “p-Cl ph” group in benzylic position + 6,7-substituted THIQ compounds 45
2.3.7.2. Biological evaluation of “p-Cl ph” group in benzylic position + 6,7-substituted THIQ compounds 48
2.3.8. Design of compounds ⑥: Benzene modification compounds 50
2.3.8.1. Synthesis scheme of Benzene modification compounds 50
2.3.8.2. Biological evaluation of Benzene modification compounds 53
2.3.9. Design of compounds ⑦: Ring expansion of THIQ scaffold compounds 55
2.3.9.1. Synthesis scheme of Ring expansion of THIQ scaffold compounds 55
2.3.9.2. Biological evaluation of Ring expansion of THIQ scaffold compounds 58
3. Conclusion 60
4. Experimental Section 61
4.1. General methods for synthesis 61
4.2. General methods for biological evaluation 61
4.2.1. Fluorescence Polarization (FP) assay 61
4.2.2. Nrf2 Nuclear Translocation assay 62
4.3. Synthesis 63
4.3.1. Synthesis of Pyrazole intermediate 63
4.3.2. Synthesis of 6,7-substituted THIQ compounds 64
4.3.3. Synthesis of 5,8-substituted THIQ compounds 98
4.3.4. Synthesis of “Me” group in benzylic position + 6,7-substituted THIQ compounds 110
4.3.5. Synthesis of “m-Cl ph” group in benzylic position + 6,7-substituted THIQ compounds 148
4.3.6. Synthesis of “p-Cl ph” group in benzylic position + 6,7-substituted THIQ compounds 182
4.3.7. Synthesis of Benzene modification compounds 217
4.3.8. Synthesis of Ring expansion of THIQ scaffold compounds 239
5. References 255

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