방선균에서 분리한 α-Glucosidase 저해물질의 구조 및 혈당상승 저해특성에 관한 연구 Studies on the structural property of an α-Glucosidase inhibitor from Streptomyces sp. and its inhabitory characteristics of blood glucose increment원문보기
당뇨병에 있어서, 기존 약물인 sulfonylurea 제제나 인슐린 등에 의해서는 식후 고혈당증(postprandial hyperglycemia)이 조절되지 못하는 인슐린 비의존형 당뇨병 환자에 있어, α-glucosidases의 저해에 의해 당뇨병의 대사 조절을 개선시킬 수 있는 신규의 α-glucosidase 저해물질에 관하여 연구하였다. 제주도 산림 토양으로부터 분리된 ...
당뇨병에 있어서, 기존 약물인 sulfonylurea 제제나 인슐린 등에 의해서는 식후 고혈당증(postprandial hyperglycemia)이 조절되지 못하는 인슐린 비의존형 당뇨병 환자에 있어, α-glucosidases의 저해에 의해 당뇨병의 대사 조절을 개선시킬 수 있는 신규의 α-glucosidase 저해물질에 관하여 연구하였다. 제주도 산림 토양으로부터 분리된 Streptomyces sp. CK-4416의 배양액으로부터 α-glucosidase 저해활성을 나타내는 물질을, Dowex 50W-2X 및 SP- Sephadex 이온 교환 크로마토그래피에 의해 분리하였으며, 정제된 2 개 성분 중 CKD 711에 관하여 실험하였다. 고분해능 FAB-MS 분석에 의하여 CKD 711의 분자식이 C_(25)H_(43)NO_(20) (MW 677.61 Da)으로 결정되었으며, 화학식은 O-[4-deoxy-4-(2, 3-epoxy-3-hydroxymethyl-4, 5, 6-trihydroxycyclo-hexane-1-yl-amino)-α- D-glucopyranosyl]- (1→4)-O-α-D-glyco-pyranosyl- (1→4)- α-D-glycopyranose으로 밝혀 졌다. 생체 외 실험에서 CKD 711은 돼지 소장 유래의 maltase 및 sucrase에 대하여 acarbose와 유사한 활성을 보인 반면 (각각 IC_(50) ; 2.5와 0.5 g/mL) α-amylase에 대해서는 acarbose에 비하여 3.2 배 낮은 저해활성을 보였다 (각각 IC_(50); 115.2 및 36.0 nM). 랫트에서 starch와 sucrose를 이용한 당부하 실험결과 CKD 711은 ED_(50)가 각각 3.07 및 1.15 mg/kg-weight로 나타난 반면, acarbose는 1.94와 1.15 mg/kg이었다. Kinetic 연구에서 CKD 711과 acarbose는 공히, 돼지 췌장 유래의 α-amylase와 maltase를 비경쟁적으로 저해하는 것으로 밝혀졌다. 생체 외, 생체 내 실험 및 kinetic 실험 결과로부터 CKD 711은 acarbose보다 췌장에서 분비되는 α-amylase에 대하여 약한 활성을 보임으로써 향후 임상적 적용 가능성이 높고, 기존의 약물보다 복부 부작용이 개선될 수 있을 것으로 예상되었다.
당뇨병에 있어서, 기존 약물인 sulfonylurea 제제나 인슐린 등에 의해서는 식후 고혈당증(postprandial hyperglycemia)이 조절되지 못하는 인슐린 비의존형 당뇨병 환자에 있어, α-glucosidases의 저해에 의해 당뇨병의 대사 조절을 개선시킬 수 있는 신규의 α-glucosidase 저해물질에 관하여 연구하였다. 제주도 산림 토양으로부터 분리된 Streptomyces sp. CK-4416의 배양액으로부터 α-glucosidase 저해활성을 나타내는 물질을, Dowex 50W-2X 및 SP- Sephadex 이온 교환 크로마토그래피에 의해 분리하였으며, 정제된 2 개 성분 중 CKD 711에 관하여 실험하였다. 고분해능 FAB-MS 분석에 의하여 CKD 711의 분자식이 C_(25)H_(43)NO_(20) (MW 677.61 Da)으로 결정되었으며, 화학식은 O-[4-deoxy-4-(2, 3-epoxy-3-hydroxymethyl-4, 5, 6-trihydroxycyclo-hexane-1-yl-amino)-α- D-glucopyranosyl]- (1→4)-O-α-D-glyco-pyranosyl- (1→4)- α-D-glycopyranose으로 밝혀 졌다. 생체 외 실험에서 CKD 711은 돼지 소장 유래의 maltase 및 sucrase에 대하여 acarbose와 유사한 활성을 보인 반면 (각각 IC_(50) ; 2.5와 0.5 g/mL) α-amylase에 대해서는 acarbose에 비하여 3.2 배 낮은 저해활성을 보였다 (각각 IC_(50); 115.2 및 36.0 nM). 랫트에서 starch와 sucrose를 이용한 당부하 실험결과 CKD 711은 ED_(50)가 각각 3.07 및 1.15 mg/kg-weight로 나타난 반면, acarbose는 1.94와 1.15 mg/kg이었다. Kinetic 연구에서 CKD 711과 acarbose는 공히, 돼지 췌장 유래의 α-amylase와 maltase를 비경쟁적으로 저해하는 것으로 밝혀졌다. 생체 외, 생체 내 실험 및 kinetic 실험 결과로부터 CKD 711은 acarbose보다 췌장에서 분비되는 α-amylase에 대하여 약한 활성을 보임으로써 향후 임상적 적용 가능성이 높고, 기존의 약물보다 복부 부작용이 개선될 수 있을 것으로 예상되었다.
It has been reported as a new pharmacological approach that the metabolic control of diabetics can be improved by the inhibition of α-glucosidases in the small intestine, as the postprandial hyperglycaemia was not adequately treated by the standard pharmacotherapy with sulfonylureas or insulin. It w...
It has been reported as a new pharmacological approach that the metabolic control of diabetics can be improved by the inhibition of α-glucosidases in the small intestine, as the postprandial hyperglycaemia was not adequately treated by the standard pharmacotherapy with sulfonylureas or insulin. It was found that several α-glucosidase inhibitors were produced by a strain of Sterptomyces which was isolated from the mountain soil of Cheju island. From the morphological characteristics by the electronmicroscopic examination, the cultural properties, and cell wall analysis using the whole-cell hydrolysates, the producing strain was designated as Streptomyces sp. CK-4416. From the culture broth, the active principles were purified by ion exchange chromatography. CKD 711 and CKD 711a were finally purified, and tested for the structure elucidation. The molecular formula of CKD 711 and CKD 711a were determined to be C_(25)H_(43)NO_(20) (MW 677.61 Da) and C_(37)H_(63)NO_(30) (MW 1001.30 Da) by HRFAB-MS analysis, respectively. From the structural analysis, it was found that the chemical structure of CKD 711 was decided to be O-[4-deoxy-4-(2,3- epoxy-3-hydroxymethyl-4, 5, 6-trihydroxycyclohexane -1-yl-amino)-α- D-glucopyranosyl] - (1→4)- O-α-D-glycopyranosyl-(1→4)-α- D-glycopyranose, and CKD 711a has 2 more glucose units which is bonded through α-(1→4)-O-glycosidic bond. In in vitro experiments, CKD 711 showed superior inhibitory effects against porcine intestinal maltase and sucrase than CKD 711a, and thereafter CKD 711 was mainly tested. CKD 711 represented similar effects to acarbose on porcine intestinal maltase and sucrase with the IC_(50) of 2.5 and 0.5 nM, respectively, whereas it showed about 3.2-fold lower α-amylase inhibitory activity (IC_(50), 115.2 nM) than that of acarbose (IC_(50), 36 nM). In rat which was fed by starch and sucrose meals, CKD 711 showed ED_(50)s of 3.07 and 1.15 mg/kg-weight respectively, whereas acarbose showed 1.94 and 1.15 mg/kg, respectively. Kinetic studies revealed that CKD 711, as well as acarbose, inhibited pancreatic α-amylase and maltase noncompetitively, which were purified from porcine small intestine. From the results of in vitro, in vivo and kinetic studies, CKD 711 exhibited superior aspects compared to acarbose, because CKD 711 showed lower inhibitory activity against pancreatic α-amylase, and consequently it is expected to show lower frequency of such abdominal adverse effects in clinical use.
It has been reported as a new pharmacological approach that the metabolic control of diabetics can be improved by the inhibition of α-glucosidases in the small intestine, as the postprandial hyperglycaemia was not adequately treated by the standard pharmacotherapy with sulfonylureas or insulin. It was found that several α-glucosidase inhibitors were produced by a strain of Sterptomyces which was isolated from the mountain soil of Cheju island. From the morphological characteristics by the electronmicroscopic examination, the cultural properties, and cell wall analysis using the whole-cell hydrolysates, the producing strain was designated as Streptomyces sp. CK-4416. From the culture broth, the active principles were purified by ion exchange chromatography. CKD 711 and CKD 711a were finally purified, and tested for the structure elucidation. The molecular formula of CKD 711 and CKD 711a were determined to be C_(25)H_(43)NO_(20) (MW 677.61 Da) and C_(37)H_(63)NO_(30) (MW 1001.30 Da) by HRFAB-MS analysis, respectively. From the structural analysis, it was found that the chemical structure of CKD 711 was decided to be O-[4-deoxy-4-(2,3- epoxy-3-hydroxymethyl-4, 5, 6-trihydroxycyclohexane -1-yl-amino)-α- D-glucopyranosyl] - (1→4)- O-α-D-glycopyranosyl-(1→4)-α- D-glycopyranose, and CKD 711a has 2 more glucose units which is bonded through α-(1→4)-O-glycosidic bond. In in vitro experiments, CKD 711 showed superior inhibitory effects against porcine intestinal maltase and sucrase than CKD 711a, and thereafter CKD 711 was mainly tested. CKD 711 represented similar effects to acarbose on porcine intestinal maltase and sucrase with the IC_(50) of 2.5 and 0.5 nM, respectively, whereas it showed about 3.2-fold lower α-amylase inhibitory activity (IC_(50), 115.2 nM) than that of acarbose (IC_(50), 36 nM). In rat which was fed by starch and sucrose meals, CKD 711 showed ED_(50)s of 3.07 and 1.15 mg/kg-weight respectively, whereas acarbose showed 1.94 and 1.15 mg/kg, respectively. Kinetic studies revealed that CKD 711, as well as acarbose, inhibited pancreatic α-amylase and maltase noncompetitively, which were purified from porcine small intestine. From the results of in vitro, in vivo and kinetic studies, CKD 711 exhibited superior aspects compared to acarbose, because CKD 711 showed lower inhibitory activity against pancreatic α-amylase, and consequently it is expected to show lower frequency of such abdominal adverse effects in clinical use.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.