臺灣博碩士論文加值系統

近年研究指出，誘導轉錄活化因子3(ATF3)表現具有改善代謝症候群之潛力。因此
，在本次研究中，針對具有光學活性之ST32db (4)進行了構效關係研究，藉此發現非掌性之7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (40c)為潛在ATF3誘導劑，且具有抑制脂肪細胞新生之能力。此外，以高脂飼料餵養之小鼠在同時給予40c之情況下，與控制組相比，體重增幅明顯趨緩。給藥結束後，40c治療組小鼠之白色脂肪重量與脂肪細胞大小亦顯著下降; 在改善血糖方面，40c 比4相比具有更優越之治療能力。另外，生化指數分析顯示，40c能進一步改善高脂飼料誘導之小鼠肝功損傷與高血三酸甘油酯，這些治療效果在4介入組小鼠中並未發現。綜上所述，作為一強力ATF3誘導劑，40c展現改善代謝症候群之治療潛力。

除上述之外，此研究亦旨於找尋非酒精性脂肪肝的治療候選藥物，以期突破臨床上無藥可用之現況。因此，本次以具有肝臟保護作用之capillarisin (5) 為模板製備一系列2-苯氧基色原酮衍生物，並將化合物與油酸同時加入Huh7細胞中，利用高內涵篩選評估抑制油滴生成之活性。經由構效關係研究發現，在苯環上含有三甲氧基基團之衍生物，會比同一環上有其他官能基之化合物具有更好的油滴抑制效果。然而，若化合物結構中，色原酮C-5位上含有羥基基團，則會展現出較明顯之細胞毒性。而在所有衍生物中，5,7-dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one (48e) 被發現為有潛力之候選藥物，其抑制油滴生成之IC50數值為32.2 ± 2.1 μM，且沒有顯著之細胞毒性。此外，48e透過刺激peroxisome proliferator-activated receptor gamma coactivator 1α之基因表現，藉此促進脂肪分解代謝以降低油滴累積，更進一步顯示其治療脂肪肝之潛力。

The induction of activating transcription factor 3 (ATF3) was identified as a promising therapeutic mechanism to overcome metabolic syndrome. In this study, a structure-activity relationship campaign on the chiral ST32db (4) led to the identification of achiral 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (40c) as a potential ATF3 inducer with anti-adipogenic features. Also, after administration of 40c, mice fed an high-fat diet demonstrated robust weight loss with reduction in the white adipose mass and fewer hypertrophic adipocytes, accompanied by a favorable glycemic profile compared to 4. Additionally, the biochemical analysis showed that 40c further improved the liver function and the plasma triglyceride profile that were absent from mice treated with 4. Altogether, 40c shows promise as an ATF3 inducer for further development to alleviate metabolic syndrome.

This study also aimed to identify a potential candidate for non-alcoholic fatty liver disease, a disorder for which no clinically approved drugs are currently available. A series of 2-phenoxychromones originating from capillarisin (5), a hepatoprotective agent was prepared and evaluated for its protective activity against lipid droplet formation in oleic acid-treated Huh7 cells through high-content screening. The compounds with trimethoxy groups on the phenyl moiety were found to harbor better activity compared to other functional groups on the same ring. However, the compounds with a hydroxy group at the C-5 position of the chromone exhibited cytotoxicity. The IC50 value of 32.2 ± 2.1 μM against lipid accumulation and absence of significant cytotoxicity make 5,7-dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one (48e) a promising candidate. Moreover, 48e reduced the accumulation of lipid droplets by upregulating peroxisome proliferator-activated receptor gamma coactivator 1α to facilitate the catabolism of fat, demonstrating its potential for further optimization to treat NAFLD.

摘要 i
ABSTRACT ii
EXTENDED ABSTRACT iii
ACKNOWLEDGMENT vii
TABLE OF CONTENTS viii
LIST OF FIGURES xi
LIST OF SCHEMES xii
LIST OF TABLES xiii
ABBREVIATION xiv
CHAPTER I. INTRODUCTION 1
1. Metabolic syndrome 1
1.1. Definitions and diagnostic criteria 1
1.2. Epidemiology and clinical implications 1
1.3. Management 2
2. Activating transcription factor 3 2
2.1. Classifications and molecular features 2
2.2. Physiological functions 3
2.3. Roles in metabolic regulations 3
3. ATF3 inducers for managing metabolic syndrome 6
3.1. Sulfuretin 7
3.2. Tanshinone IIA, ST32da and ST32db 7
4. Fatty liver diseases 9
4.1. Definitions and classifications 9
4.2. Epidemiology and clinical implications of non-alcoholic fatty liver disease 9
4.3. Management of non-alcoholic fatty liver disease 10
5. Lipid metabolism in the liver 10
5.1. Uptake of free fatty acids 11
5.2. De novo lipogenesis 11
5.3. TG exportation 12
5.4. Fatty acid oxidation 12
6. 2-Phenoxychromones 13
6.1. Natural 2-phenoxychromones 13
6.2. Capillarisin 15
CHAPTER II. AIMS 17
CHAPTER III. MATERIALS AND METHODS 18
1. Chemistry 18
1.1. Synthesis of the derivatives of ST32db (4) 18
1.2. Synthesis of the derivatives of capillarisin (5) 31
2. In vitro analysis 44
2.1. Cell culture 44
2.2. Compound treatment 44
2.3. Real-time polymerase chain reaction (PCR) 45
2.4. Cytotoxic assay 46
2.5. Lipid droplet assay 46
2.6. Western blot analysis 46
2.7. Oil-red O staining 47
3. Animal study 47
3.1. Glucose tolerance test and insulin tolerance test 47
3.2. Measurement of biochemical parameters 47
3.3. Hematoxylin and Eosin stain 48
4. Statistical analyses 48
CHAPTER IV. RESULTS 49
1. Activating transcription factor 3 inducers for managing metabolic syndrome 49
1.1. Chemistry 49
1.2. Activating transcription factor 3-induction ability of target molecules in 3T3-L1 cells 53
1.3. Western-blot analysis and Oil-red O staining 55
1.4. Compound 40c protected mice from high-fat diet-induced metabolic dysregulation 56
2. 2-Phenoxychromones for managing non-alcoholic fatty liver disease 59
2.1. Chemistry 59
2.2. Lipid-lowering effects of 2-phenoxychromones in Huh7 cells 61
2.3. mRNA expression analyses of Huh7 cells after treatment with 48e 63
CHAPTER VII. DISCUSSION 66
1. Activating transcription factor 3 inducers for managing metabolic syndrome 66
2. 2-Phenoxychromones for managing non-alcoholic fatty liver disease 68
CHAPTER V. CONCLUSION AND FUTURE WORK 71
REFERENCES 72
SUPPLEMENTARY INFORMATION 81

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