| Abbreviations | 第5-11页 |
| Abstract | 第11-13页 |
| 摘要 | 第14-18页 |
| 1、General Overview | 第18-49页 |
| 1.1 Introduction | 第18-26页 |
| 1.2 Uniqueness of HDAC8 as compared with other Class Ⅰ Zn~(2+)-dependent HDAC isoforms | 第26-29页 |
| 1.3 Active site topology | 第29-32页 |
| 1.4 Proposed catalytic mechanisms | 第32-33页 |
| 1.5 Biological significance of HDAC_s and HDAC_s inhibitors | 第33-36页 |
| 1.6 HDAC8 and diseases | 第36-39页 |
| 1.7 Substrate specificity and selectivity of HDAC8 compared with other Zn~(2+)-dependent HDAC_s | 第39-41页 |
| 1.8 Established bioassay for quantification of human Zn~(2+)-dependent protein deacetylases | 第41-45页 |
| 1.9 Impact of HDAC8/HDAC_s research on drug design | 第45-47页 |
| 1.10 Clinical implications of HDAC inhibitors (HDACi) | 第47-49页 |
| 2、Future Prospects of HDAC8/HDAC_s Activators | 第49-65页 |
| 2.1 Background | 第49-54页 |
| 2.2 HDAC8 activators and diseases | 第54-60页 |
| 2.3 Statement of problems and objectives | 第60-62页 |
| 2.4 Design rationale/aim | 第62-65页 |
| 3、Experimentations | 第65-84页 |
| 3.1 Materials and equipment/instruments | 第65-66页 |
| 3.2 Synthesis, purification and characterization of compounds | 第66-71页 |
| 3.2.1 Synthesis, purification and characterization of compounds 1, 3, and 5 (see Scheme2.11) | 第66-67页 |
| 3.2.2 Synthesis, purification and characterization of compounds 2, 4, and 6 (see Scheme2.12) | 第67-69页 |
| 3.2.3 Synthesis, purification and characterization of compound 7 (see Scheme 2.13) | 第69-71页 |
| 3.3 Synthesis of AMC-less substrates for both HDAC8 and HeLa nuclear extract | 第71-78页 |
| 3.4 HPLC-based HDAC8 enzymatic assay using AMC-containing substrate | 第78页 |
| 3.5 HPLC-based HDAC8 activation assay using AMC-less substrate | 第78-79页 |
| 3.6 HPLC-based HeLa nuclear extract activation assay using AMC substrate | 第79-80页 |
| 3.7 HPLC-based HeLa nuclear extract activation assay using AMC-less substrate(A_c-RHK(A_c)K(A_c)-CO-NH_2) | 第80-81页 |
| 3.8 Measurement of K_m of HDAC8 AMC-less substrate in the presence and absence of thebest activator, compound 7 | 第81-83页 |
| 3.8.1 Measurement of K_m of HDAC8 AMC-less substrate in the absence of compound | 第81-82页 |
| 3.8.2 Measurement of K_m of HDAC8 AMC-less substrate in the presence of compound | 第82-83页 |
| 3.9 Measurement of K_m of AMC substrate in the presence and absence of the best activator, compound 7 | 第83-84页 |
| 3.9.1 Measurement of K_m of AMC substrate in the absence of compound 7 | 第83页 |
| 3.9.2 Measurement of K_m of AMC substrate in the presence of compound 7 | 第83-84页 |
| 4、Results and Discussions | 第84-98页 |
| 4.1 Structural characterization of compounds 1-7 | 第84-89页 |
| 4.2 HDAC8 enzymatic assay with AMC substrate | 第89-91页 |
| 4.3 HDAC8 enzymatic assay with its AMC-less substrate | 第91-93页 |
| 4.4 HeLa nuclear extract enzymatic assay with AMC substrate | 第93-94页 |
| 4.5 HeLa nuclear extract enzymatic assay with AMC-less substrate | 第94-96页 |
| 4.6 Measurement of K_m of HDAC8 AMC and AMC-less substrates in the presence andabsence of compound 7 | 第96-98页 |
| 5、Conclusion and Recommendation | 第98-100页 |
| 5.1 Conclusion | 第98-99页 |
| 5.2 Recommendation | 第99-100页 |
| References | 第100-114页 |
| Appendix | 第114-133页 |
| ACKNOWLEDGEMENTS | 第133-134页 |
| Publication | 第134页 |
