合成具有活性，選擇性之鈉依賴型葡萄糖共同運輸通道抑制劑之碳-芳香環-D-呋喃葡萄糖苷作爲治療第二型糖尿病之藥物

Synthesis of C-aryl D-glucofuranosides as Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for Type 2 Diabetes Treatment

劉雅雯(Ya-Wen Liw)

指導教授 ： 梁碧惠

國立臺灣大學/醫學院/藥學研究所/碩士(2011年)

https://doi.org/10.6342/NTU.2011.00453

摘要

目前大多數用於治療第二型糖尿病(T2DM)的藥物，並不足以維持血醣於理想範圍，即糖化血色素(HbA1c)數值小於7%。因此，亟需發展有別於目前治療機轉的其他藥物。第二型鈉依賴葡萄糖轉運蛋白(SGLT2)由672個氨基酸所組成，獨特地表現於腎近端小管S1部分，以高容量，低親和力的方式將大部分存在在腎小球濾液裏的腎糖再吸收， 因此推測抑制SGLT2能夠降低血糖濃度以達到血糖控制的效果。
先導化合物，Dapagliflozin 7，具有碳–芳香環-六環葡萄糖苷之結構，可選擇性與SGLT2結合但不被轉運，是一個活性極高的抑制劑。先前已有研究指出，六環的N-glucosides, S-glucosides, thio-C-glucosides and dioxa-bicyclo-[3.2.1]octane皆對SGLT2有抑制的效果，但並未有文獻針對呋喃葡萄糖苷（水溶液中的糖有1%是由呋喃葡萄糖苷組成的）的結構進行過討論。因此我們設計並合成了一系列由碳-芳香環-D-呋喃葡萄糖苷組成的化合物。兩個關鍵的中間物，分別為D -葡萄糖酸-γ-內酯46為偶聯反應所用及C -苯甲醛-葡萄糖65為格氏反應所用。
利用穩定表達hSGLT1的COS-7細胞，我們針對化合物32a-32r進行了14C-AMG攝取抑制測試；然而結果顯示這些分子在5μM的濃度中，對hSGLT1並無抑制效果。另外，針對hSGLT2的細胞測試仍在進行中。

關鍵字

第二型糖尿病 ； 第二型鈉依賴葡萄糖轉運蛋白 ； dapagliflozin ； 呋喃葡萄糖苷碳-芳香環-D-呋喃葡萄糖苷

並列摘要

A wide range of medications available for type 2 diabetes (T2DM) are inadequate to maintain the glycemic control at HbA1c <7%, hence development of novel drug with different mechanism of action is desirable. Type 2 sodium-dependent glucose co-transporter (SGLT2) is a 672-amino acid, high capacity, low affinity transporter express nearly exclusively in the S1 segment of the renal proximal tubule. Since SGLT2 mediates the majority of renal glucose reabsorption from the glomerular filtrate, inhibiting SGLT2 is believed to be able to decrease the glucose level to achieve glycemic control.
Dapagliflozin (7), a leading compound with a structure of C-arylglucoside, can bind to but not be transported by SGLT2, andacts as a potent and selective SGLT2 inhibitor. Various glycoform, such as N-glucosides, S-glucosides, thio-C-glucosides and dioxa-bicyclo-[3.2.1]octane have been studied for their effect on SGLT2 inhibitions but no report was published on glucofuranosides which contain 1% composition of sugars in aqueous solution. Herein, we designed and synthesized a series of novel (1S)-1,4-anhydro-1-C-aryl-D-glucitol derivatives. To get these compounds, 2 key intermediates—perbenzylated D-glucono-gamma-lactone 46 and C-benzylaldehyde glucoside 65, were synthesized and they were sequentially subjected to the coupling reaction and Grignard reaction to afford the desired structures.
The inhibitory effect of compounds 32a-32r on the uptake of [14C]-AMG were tested in COS-7 cell stably expressing hSGLT1, the results showed no inhibitory activity of these compounds at 5 μM against hSGLT1. Further study on the cell-based assay of hSGLT2 is still in progress.

並列關鍵字

Type 2 Diabetes Mellitus (T2DM) ； Sodium Glucose co-transporter 2 (SGLT2) ； glucofuranosides ； (1S)-1,4-anhydro-1-C-aryl-D-glucitol

參考文獻

1. King, H.; Aubert, R. E.; and Herman, W.H. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care 1998, 21, 1414-1431.

3. Kaiser, N.; Leibowitz, G. J. Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. J. Pediatr. Endo. Metab. 2003, 16, 5-22.

4. Morrish, N. J.; Wang, S. L.; Stevens, L. K.; Fuller, J. H.; Keen, H. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 2001, 44, S14–S21.

5. Stratton, I. M.; Adler, A. I.; Neil, H. A.; Matthews, D. R.; Manley, S. E.; Cull, C. A.; Hadden, D.; Turner, R. C.; Holman, R. R. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000, 321, 405-412.

6. Bell, D. S. H. Type 2 diabetes mellitus: What is the optimal treatment regimen? Am. J. Med. 2004, 116 (5 Suppl. 1), 23S-29S.