α-Glucosidase Inhibitor 2016.05.20 김연수

Contents Introduction Chemistry Biological results and discussion Evaluation of N- or 1-C-Butyl-LAB and –DNJ Derivatives as Glycosidase Inhibitors Optimization of the α-1-C-Alkyl Chain Length Structural Modification of Whole Cell N-Linked Oligosaccharides Carbohydrate Loading Test Docking Studies of -1-C-Butyl-LAB and Miglitol with Intestinal Maltase Conclusion

Introduction Diabetes mellitus - 인슐린의 분비량이 부족하거나 정상적인 기능이 이루어지지 않는 등의 대사질환의 일종 제1형 당뇨병 (Insulin dependent diabetes mellitus : IDDM) 제2형 당뇨병 (Non-insulin dependent diabetes mellitus : NIDDM) – 초기증상으로 postprandial hyperglycemia(식후고혈당) 나타남

Introduction α-glucosidase inhibitor - α-glucosidase라는 효소를 억제하여 이당류의 가수분해를 억제하여 소장으로의 당흡수를 저해하는 약물 - postprandial hyperglycemia(식후고혈당)를 예방하는 antidiabetic agent

Introduction N-containing α–glucosidase inhibitors Carbasugar-based inhibitors – acarbose, voglibose Iminosugar-based inhibitors - miglitol LAB

Chemistry

Chemistry

Chemistry

Chemistry

Biological results and Discussion 1. Evaluation of N- or 1-C-Butyl-LAB and –DNJ Derivatives as Glycosidase Inhibitors

Biological results and Discussion 1. Evaluation of N- or 1-C-Butyl-LAB and –DNJ Derivatives as Glycosidase Inhibitors

Biological results and Discussion 2. Optimization of the α-1-C-Alkyl Chain Length LAB derivatives DNJ derivatives

Biological results and Discussion 2. Optimization of the α-1-C-Alkyl Chain Length

Biological results and Discussion 3. Structural Modification of Whole Cell N-Linked Oligosaccharides Glycoprotein - 당과 단백질이 공유결합하여 만들어진 복합단백질 - 세포간의 인식 및 상호작용, 세포의 발생, 분화, 형태형성, 이동 및 사멸 등 세포의 생명활동에 중요한 역할 - ER에서 합성 - glycoprotein의 oligosaccharide는 ER-glucosidase 유발

Biological results and Discussion 4. Carbohydrate Loading Test

Biological results and Discussion 5. Docking Studies of -1-C-Butyl-LAB and Miglitol with Intestinal Maltase

Biological results and Discussion 5. Docking Studies of -1-C-Butyl-LAB and Miglitol with Intestinal Maltase

Biological results and Discussion 5. Docking Studies of -1-C-Butyl-LAB and Miglitol with Intestinal Maltase

Conclusions Design and synthesis of a series of α-1-C-alkylated LAB derivatives by AAA, RCM,and Negishi cross-coupling as key reactions. Among the produced compounds, α-1-C-butyl-LAB showed potent inhibitory activity toward intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.02, 4.7, 0.032μM, respectively. Therefore α-1-C-butyl-LAB represents a new class of promising compounds that have the potential for treating postprandial hyperglycemia.