| Summary: | 碩士 === 台北醫學院 === 藥學研究所 === 89 === 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.
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