Caffeoylquinic acid (CQA) is one of the phenylpropanoids found in coffee beans, sweetpotato, propolis, and other plants. [1][2][3] CQA derivatives have a variety of bioactivities such as antioxidant, antibacterial, anticancer, antihistamic, and other biological effects. [4][5][6][7][8] In our previous study, we demonstrated that 3,5-di-O-caffeoylquinic acid (3,5-di-CQA) inhibits amyloid b 1-42 -induced cellular toxicity on human neuroblastoma SH-SY5Y cells, and increases the mRNA expression level of glycolytic enzyme, phosphoglycerate kinase 1 (PGK1) and the intracellular ATP level. 9) We also indicated that 3,5-di-CQA administration induced the improvement of spatial learning and memory on senescence accelerated-prone mice 8 (SAMP8), and the overexpression of PGK1 mRNA level.9) Moreover, we found that 3,4,5-tri-Ocaffeoylquinic acid (3,4,5-tri-CQA) showed higher accelerating activity on ATP production than 3,5-di-CQA, suggesting that the number of caffeoyl groups is important for the activity (unpublished observation). However, structure-activity relationship of CQAs on the accelerating activity on ATP production are not clarified in detail.CQAs are classified into various derivatives, according to the number or the position of caffeoyl groups. The syntheses of mono-CQA derivatives including one caffeoyl group were reported by Sefkow et al. 10,11) There were, however, few reports about synthesis of CQA derivatives with more than two caffeoyl groups. Accordingly, we planed the syntheses of the CQA derivatives with more than two caffeoyl groups. We also evaluated the intracellular ATP level in SH-SY5Y cells treated with these derivatives for structure-activity relationship on the accelerating activity on ATP production.
Results and DiscussionSynthesis of 1,4,5-tri-O-Caffeoylquinic Acid CQA derivatives that caffeoyl groups bind to 3-, 4-, and 5-hydroxyl groups in quinic acid are found abundantly in natural resources. On the other hand, the derivatives that caffeoyl group binds to 1-hydroxyl group were rare in them. It was also interested whether they have the accelerating activity on ATP production. So, we initially synthesized 1,4,5-tri-O-caffeoylquinic acid (1,4,5-tri-CQA) as shown in Chart 1. Isopropyridene quinide (2) was synthesized from commercially available quinic acid (1), according to previously reported method.12) Di-O-acetylcaffeoyl chloride (b) was used for followed esterification reaction. Acid chloride b was obtained from commercially available caffeic acid (a) in two steps, acetylation with Ac 2 O in pyridine and chlorination with SOCl 2 . 10) Isopropyridene quinide (2) reacted with acid chloride b in pyridine and CH 2 Cl 2 to afford ester 3 in 50% yield.11) The acetonide group of 3 was selectively cleaved with 90% trifluoroacetic acid (TFA) to give diol 4 in 61% yield. Diol 4 was heated with five equivalents of c under reflux in benzene for 24 h to afford tri-ester 5 in 86% yield. Hydrolysis of all protecting groups was accomplished with 1 M HCl at room temperature to obtain 1,4,5-tri-CQA (6) in 46...
