NF-κB 저해제로써 Thiazole을 포함한 Chlorogenic Acid 유도체들의 합성과 생물학적 평가 및 대사 안정성 평가

다국어 초록 (Multilingual Abstract)

Chlorogenic acid (CGA) is natural polyphenol compound found in various agricultures such as coffee, beans, particularly Lonicera japonica. CGA is formed by esterification of caffeic acid and quinic acid. According to previous studies, CGA exhibits various biological properties like anti-bacterial, anti-inflammatory, anti-oxidant, and anti-carcinogenic activities. Among these activities, anti-inflammatory activity is applied to inflammatory diseases including sepsis and septic shock. Despite decades of efforts, sepsis and septic shock isn't completely understood and defined. So many patients suffering these diseases lie on high mortality because of lack of the effective therapies and treatment. In this situation, CGA may be a potential therapeutic drug for inflammatory diseases by inhibiting the nuclear translocation of Nuclear factor (NF)-κB. NF-κB is one of the most important transcription factors involved in inflammatory process by regulating the expression of pro-inflammatory mediators such as cytokines, chemokines, adhension molecule. Thus, regulation of NF-κB activity may be inflammatory diseases therapeutic target. Considering that CGA may be effective for the prevention and treatment of inflammatory diseases, we synthesized CGA derivatives possessing thiazole to have drug-like properties. They are evaluated for identifying inhibitory activity of NF-κB activation related to inflammation and inhibitory activity of α-MSH activation related to skin-whitening effect. Also we estimated their metabolic stability based on in vitro DMPK assays. Some of derivatives have effective activity compared with CGA, but DMPK assays show that all of CGA derivatives are unstable. Therefore, converting of derivatives structure is necessary to solve stability problem and have more good biological activity. Additional experiment is in progress to design and synthesize CGA derivatives for searching improved compounds.

목차 (Table of Contents)

• Ⅰ. Introduction 8
• Ⅱ. Design and Chemistry 12
• 1. Design 12
• 2. Chemistry 13
• 3. Biological evaluation 21
• 4. Metabolic stability 24
• Ⅲ. Results and discussion 30
• Ⅳ. Experimental section 32
• 1. General introduction 32
• 2. Biological evaluation 33
• 3. DMPK assay 35
• 4. Synthetic experiments 36
• Ⅴ. References 59