α-Glucosidase Inhibitory Constituents from Terminalia chebula Fruits
가자나무 열매에서 분리한 알파 글루코시데이즈 억제 성분
- Dong Young Lee
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- Terminalia chebula; Combretaceae; hydrolysable tannin; polyhydroxytriterpene; HPLC-based activity profiling
- 학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2017. 2. 성상현.
- Type 2 diabetes mellitus (T2DM), known as non-insulin-independent diabetes, is a chronic metabolic disorder which is due to insulin-resistance in the tissues. As a result, insulin resistance leads to elevated blood glucose levels, which can damage many of the organs. One of the therapeutic approaches for treating T2DM is to alleviate postprandial hyperglycemia. This is achieved by suppressing the glucose absorption from the gut by inhibiting intestinal carbohydrate digesting enzymes such as α-glucosidase. In this study, to isolate new α-glucosidase inhibitory compounds efficiently, an HPLC-based activity profiling with dereplication was carried out. HPLC-based activity profiling of an extract from Terminalia chebula fruits enabled the isolation and identification of thirteen compounds including four new ones (3 and 11-13). Among the thirteen compounds, compounds 4-13 obtained from the active microfractions exhibited potent inhibitory activities against Bakers yeast α-glucosidase. These results confirm that HPLC-based activity profiling is an effective method for isolating new bioactive compounds.
Moreover, to investigate the constituents of T. chebula fruits, further isolation was carried out. As a result, fifty-three compounds including thirty-six hydrolysable tannins and seventeen polyhydroxytriterpenes were further isolated from a methanolic extract of T. chebula fruits. A total of sixty-six compounds, including nine new hydrolysable tannins (3, 11-13, 18, 20, 21, 23, and 24) and three new polyhydroxytriterpene derivatives (51, 52, and 66), were finally isolated and identified.
The inhibitory activities of all the isolated compounds against Bakers yeast α-glucosidase were tested, and as a result, twenty-four compounds (4-13, 16-18, 22, 25, 43-49, 60, and 61) exhibited inhibitory activities. Among these compounds, compounds 8, 11, and 12 showed significant inhibitory activity (IC50 8.3, 6.4, and 2.9 μM, respectively). Furthermore, all the compounds were tested for their inhibitory activity against rat intestinal α-glucosidase, porcine pancreatic α-amylase, and PTP-1B. In the case of rat intestinal α-glucosidase and porcine pancreatic α-amylase, compound 8 showed the potent inhibitory activity (IC50 17.3 and 13.4 μM, respectively) which was comparable to the positive control, acarbose. In the case of PTP-1B, compounds 8 and 60 exhibitied the most significant inhibitory activities (IC50 2.0 and 10.3 μM, respectively) among the hydrolysable tannins and polyhydroxytriterpene derivatives, respectively.