Title Page
Contents
LIST OF ABBREVIATIONS 11
LIST OF ¹H and ¹³C NMR 13
ABSTRACT 14
I. Introduction 16
1. Histone deacetylases 16
1.1. HDAC6: class II deacetylase 20
1.2. HDAC8: class I deacetylase 20
2. HDAC related diseases 20
3. HDAC inhibitors 22
3.1. FDA approved HDAC inhibitors 22
3.2. Selective HDAC6 or 8 inhibitors 24
II. Drug Design 27
1. Strategies of targeting HDAC6/8 27
2. Previous studies 29
3. Structure modification 31
III. Result and Discussion 32
1. Structure synthesis 32
1.1. Synthesis of quinoline analogs I 32
1.2. Synthesis of quinoline analogs II 36
2. In vitro HDAC enzyme activity assay 38
3. Molecular docking analysis 39
4. In vitro microsomal stability assay 42
IV. Conclusion 46
V. Materials and Methods 47
VI. References 70
APPENDICES 74
ABSTRACT IN KOREAN 80
Table 1. Classification of histone deacetylases (HDACs) 19
Table 2. Comparison of IC50 values and Microsomal stability against...[이미지참조] 29
Table 3. Activity of quinoline analogs against HDAC6 and 8. 38
Table 4. In vitro microsomal stability of compounds 9a, 9b 42
Figure 1. Histone acetylase and deacetylase. 16
Figure 2. HDAC classification 18
Figure 3. FDA approved HDAC inhibitors. The cap group, linker and the... 23
Figure 4. Different HDAC inhibitors. The zinc binding group (ZBG) are 24
Figure 5. Structures of reported HDAC6 and HDAC8 selective inhibitors. 25
Figure 6. Structures of HDAC pharmacophore. 27
Figure 7. Unique binding pocket of HDAC6 (PDB code: 5EDU) and... 28
Figure 8. Binding mode of SPA3408 and SPA3437 in HDAC8 active... 30
Figure 9. Drug design-Quinoline analogs I, II 31
Figure 10. Binding mode of compound 9b, 20 and SPA 3437 in HDAC6... 40
Figure 11. Binding mode of SPA3408 and compound 29a in HDAC8... 41
Scheme 1-1. Reaction conditions: (i) (Bromomethyl)cyclopropane,... 33
Scheme 1-2. Reagents and conditions: (a) 33% KOH, approved or... 34
Scheme 2. Reagents and conditions: (a) Acetic anhydride, sulfuric... 35
Scheme 3. Reagents and conditions: (a) Acetic Acid, Malonic acid... 36