臺灣博碩士論文加值系統

Table of Contents
Table of Contents i
List of Figures iii
List of Table iv
ACKNOWLEDGEMENT v
Abbreviation viii
Abstract x
1. Introduction 1
1.1. Colorectal cancer 1
1.2. Colorectal cancer and tumor microenvironment 3
1.3. Histone deacetylases 5
1.4. Histone deacetylases inhibitors 8
1.5. Heat shock protein 90 (HSP90) 10
1.6. HDAC6/HSP90 inhibition 11
1.7. Phosphate conjugate prodrugs and cancer therapy 13
1.8. HDAC6/HSP90 dual inhibitor (compound 17) 15
2. Research gap and motivation 20
3. Objective of study 21
4. Materials and methods 22
4.1. Rational drug design 22
4.2. Chemistry 24
Scheme 1: Synthesis of 2,4-bis(benzyloxy)-5-isopropylbenzoic acid (compound 6) 25
Scheme 2: Synthesis of intermediate 8 26
Scheme 3: Synthesis of MTP0G662-Phosphate prodrug (compound 16) 28
5. Results and Discussion 30
6. Conclusion 37
7. Experimental procedure 38
7.1. Experimental instrument and equipment 38
7.2. Experimental solvents and reagents 39
7.3. Experimental section 41
References 54
Appendix 61
Appendix 1: Nuclear magnetic resonance (NMR) spectrum. 61
Appendix 2: High performance liquid chromatography (HPLC) spectrum 77
Appendix 3: High resolution mass spectrometry (HRMS) 78

List of Figures
Figure 1.1: A simplified Illustration showing how immune suppressive cells in TME assist colorectal cancer cells escape[18]. 5
Figure 1.2: Mechanism of histone acetylation, HDAC-mediated deacetylation, and HDAC inhibition in the regulation of chromatin structure and gene transcription[21]. 6
Figure 1.3: Chemical structures of FDA-approved histone deacetylase (HDAC) inhibitors[24]. 9
Figure 1.4: Schematic overview of HDAC6/Hsp90 inhibition and its downstream effects[42]. 12
Figure 1.5: In vivo bioactivation of prodrugs by enzymatic and/or chemical transformations[51]. 15
Figure 1.6: Structure of HDAC6/HSP90 dual inhibitor (compound 17)[55]. 16
Figure 4.1: Structure-Based Pharmacophore Merging Leading to a Dual HSP90-HDAC Inhibitory Scaffold, compound 17[26]. 23
Figure 4.2: Structural modification of compound 17 to generate the phosphate prodrug compound 16 (MPT0G662-Phosphate). 23

List of Table
Table 1: Summarizes the classification, localization, cofactors, and functions of HDAC family member[24]. 7

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