Structure-Activity Relationship of Caffeoylquinic Acids on the Accelerating Activity on ATP Production

Abstract

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on ATP production than 3,5-di-CQA, suggesting that the number of caffeoyl groups is important for the activity (unpublished observation).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...

Inhibition of Amyloid β Aggregation by Acteoside, a Phenylethanoid Glycoside

“…[4][5][6] We have also reported that a CQA treatment improved the spatial learning memory in senescence acceleratedprone mice 8 by increasing the mRNA expression of phosphoglycerate kinase 1. 4) We have recently reported that CQAs strongly inhibited the aggregation of A42 and suppressed the transformation into -sheet and cytotoxicity against human neuroblastoma cells of A42.…”

Induction of Hepatocyte Growth Factor Production in Human Dermal Fibroblasts by Caffeic Acid Derivatives

“…In our previous study, we reported that neuroprotective effect from Aβ42-induced cytotoxicity of CQAs, [19][20][21] and the inhibition of the amyloid β aggregation by CQAs and acteoside (2). 24,25) Combined with these previous studies and this study about HGF promoting activity of CQAs such as 4,5-di-O-caffeoylquinic acid (1) and acteoside (2), they have a potential to cure neurodegenerative diseases like AD, the evidence that having not only the direct protect activity against amyloid β toxicity but also the promoting activity of HGF.…”

“…19) We also reported that CQAs treatment improved spatial learning memory on senescence accelerated-prone mice 8 through increasing the mRNA expression of phosphoglycerate kinase 1. 20,21) Furthermore, acteoside (2) found in natural resources of Orobanche minor, olive, and other plants, 22) is reported that it protects human neuroblastoma SH-SY5Y cells against amyloid β cell injury by protecting reactive oxygen species (ROS) production and modulating apoptotic signal pathway.…”

“…Materials 4,5-Di-O-caffeoylquinic acid (1) was synthesized as previously described, 19) while caffeic acid (3), hydroxytyrosol (4), and quinic acid (5) were purchased from Sigma-Aldrich Co., LLC (St. Louis, MO, U.S.A.). On the other hand, acteoside (2) was isolated from the roots of O. minor in * To whom correspondence should be addressed.…”

The in vivo hepato-recovery effects of the polyphenol-rich fermented food Xeniji™ on ethanol-induced liver damage

“…The most abundant polyphenols in Xeniji were 5-O-caffeoylquinic acid, followed by 3-O-caffeoylquinic acid and sakuranetin. 5-O-Caffeoylquinic acid and 3-O-caffeoylquinic acid are two phenolic acids that have been previously reported to induce various bioactivities including antioxidant, antibacterial, antitumor, antihistaminic 18 and antiobesity 19 effects. In addition, both 5-O-caffeoylquinic acid and 3-O-caffeoylquinic acid were also reported to have an in vitro liver protective effect against carbon tetrachloride (CCl 4 ) challenges.…”