Isoferulic Acid類似物之合成及其降血糖作用之研究

Studies on the Synthesis and Hypoglycemic Activity of Isoferulic Acid Analogues

蕭宏安(Hong-An Hsiao)

指導教授 ： 陳繼明

臺北醫學大學/藥學院/藥學研究所/碩士(2001年)

摘要

最近，本學系實驗室發現由中藥北升麻（Cimicjfuga dahurica）分離出成分之isoferulic acid（1）具有降血糖的活性，其活性對於第一型糖尿病（IDDM）較第二型糖尿病（NIDDM）顯著；且isoferulic acid對於健康老鼠的血糖不會影響。其降血糖作用之機轉係由於增加體內骨骼肌對葡萄糖之利用以及降低肝臟對肝醣之分解所致。今擬以isoferulic acid為先導化合物進行化學構造修飾，合成一系列isoferulic acid衍生物，並研討其化學構造變化對降血糖藥效之影響，以期作為設計新型降血糖前導藥物之重要參考。 Isoferulic acid（1）及其第三位氧烷基取代之類似物是由Knoevenagel縮合反應製備而得，將malonic acid及不同的第三位氧烷基取代之benzaldehydes（例如isovanillin、veratraldehyde、piperonal及化合物5、7、9），在pyridine及少許piperidine的環境下進行縮合反應，可得一系列第三位氧烷基取代之類似物1、3、4、6、8及10。第三位氧acyl基團取代之類似物11及12是將isoferulic acid於酸性下與無水酸酐反應而得。第四位氧烷基取代之類似物14及16是將各種不同的第四位氧烷基取代之benzaldehydes（13及15）與malonic acid進行縮合反應而得。酯類類似物17∼19則是由isoferulic acid與不同的醇類進行酯化反應而得。3-Hydroxy-4-methoxycinnamoyl chloride與不同的一級或二級胺類進行縮合反應，可得到醯類類似物20∼25。直接將反式isoferulic acid以紫外光照射，進行光化學反應，則可得順式類似物26。將isoferulic acid進行氫化反應可得到飽和類似物27。若將isoferulic acid methyl ester（17）與diazomethane及palladium (II) acetate進行環化反應，再將酯類水解即得環丙烷類似物29。α-甲基類似物30可由methyl malonic acid與3-hydroxy-4-methoxy benzaldehyde進行縮合反應而得。以上共合成1、3、4、6、8、10∼12、14、16∼27、29及30等共23個類似物，各別之化學構造均經融點測定、紅外光譜、氫譜、質譜、碳譜及元素分析確認其化學構造。 本研究初步選擇1∼4、6、11、17、20、22、24、25、27、29及30等共15個化合物進行降血糖活性試驗。經由streptozotocin誘導糖尿病鼠的離體肌母細胞對葡萄糖吸回作用的結果顯示，化合物6、11、16、22及24的作用較isoferulic acid（1）為佳，其中又以化合物6及11對降血糖活性的提升最為顯著。由化學結構與活性關係部分之結果來看，苯環上第四位-OCH3及不飽和雙鍵乃活性所必需，而三級醯胺、第三位氧乙基取代或第三位氧acyl基團所取代之類似物亦能增強其降血糖活性。

關鍵字

糖尿病 ； 降血糖作用 ； Isoferulic acid

並列摘要

Recently, isoferulic acid isolated from the rhizome of Cimicjfuga dahurica Maxim.(Ranunculaceae) has been identified to have in vivo antihyperglycemic activity in our laboratory. The effect for lowering of plasma glucose by isoferulic acid in IDDM rats is more active than that in NIDDM rats. Furthermore, the plasma glucose in normal rats is not markedly influenced by isoferulic acid under similar treatment. The antihyperglycemic mechanism is through the enhancement of glucose utilization in peripheral tissues and a reduction of hepatic gluconeogenesis. In order to study the structure and activity relationship (SAR) of isoferulic acid (1), a series of isoferulic acid analogues are prepared and their antidiabetic activities are evaluated. Isoferulic acid (1) and its 3-O-alkyl analogues are prepared by Knoevenagel condensation. Condensation of malonic acid with various 3-O-alkyl benzaldehydes (e.g. isovanillin, veratraldehyde, piperonal, compound 5, 7, and 9) in the presence of pyridine and a trace of piperidine gave the 3-O-alkyl analogues 1, 3, 4, 6, 8, and 10. The 3-O-acyl analogues, 11 and 12, are prepared by isoferulic acid and anhydrides in acid medium. The 4-O-alkyl analogues 14 and 16 are prepared by condensation of various 4-O-alkyl benzaldehydes (13 and 15) and malonic acid. The ester analogues 17∼19 are prepared by esterification of isoferulic acid with various alcohols. Condensation of 3-hydroxy-4-methoxycinnamoyl chloride with various primary and secondary amines gave the amide analogues 20∼25. The cis-form analogue 26 is generated by photochemical reaction with direct UV irradiation of the trans-isoferulic acid. Catalytic hydrogenation of isoferulic acid gave the dihydroisoferulic acid 27. Cyclopropane analogue 29 was prepared by treated isoferulic acid methyl ester (17) with diazomethane and palladium (II) acetate followed with hydrolysis. The α-methyl analogue 30 is prepared by the condensation of methyl malonic acid and 3-hydroxy-4-methoxybenzaldehyde. Twenty three products were prepared including 1, 3, 4, 6, 8, 10∼12, 14, 16∼27, 29, and 30. All these analogues were characterized by M.P., IR, 1H-NMR, mass spectrometry, 13C-NMR and element analysis. Initially, 15 analogues including 1∼4, 6, 11, 16, 17, 20, 22, 24, 25, 27, 29, and 30 were selected to evaluate their antidiabetic activities. The glucose uptake study of soleus muscle cells from streptozotocin induced diabetic rats shows that 6, 11, 16, 22, and 24 were more active than that of isoferulic acid (1). Among these compounds, 6 and 11 have the most remarkable antidiabetic activities. The preliminary results of structure and activity relationships show that the 4-OCH3 on aromatic ring and the unsaturated double bond are essential for antidiabetic activities. The tertiary amides, the 3-O-ethyl or 3-O-acetyl substitutions also enhance the activity.

並列關鍵字

Diabetics ； Hypoglycemic activity ； Isoferulic acid

參考文獻

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