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accumulation at low doses. In accordance with Zhao et al.,20 we
hypothesize that this novel series of paeonol derivatives follows
the paeonol pathway to regulate lipid accumulation by upre-
gulating the nuclear translocation of LXRa, which enhances the
mRNA and protein expression of ABCA1, thereby reducing the
accumulation of cholesterol. The results indicated that
compounds 6a and 7a are potentially suitable antiatherogenic
compounds for future drug development.
Fig. 4 7a in low-dose treatment exhibited good activity as paeonol in
high-dose. A. Fold changes of lipid accumulation in macrophages by
fluorescent assay. B. Representative fluorescent microscopy images of
lipid accumulation after incubation with or without Dil-oxLDL in
macrophages pretreated with paeonol or 7a. Data are mean ꢁ S.E.M.
from three independent experiments.
Notes and references
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The structure–activity relationship (SAR) of the compounds
was evaluated based on our results. Among the series of imine-
conjugated paeonol derivatives, the compound 4c bearing a
propyl group was the most efficacious, compared with those
bearing methyl, ethyl, and isopropyl groups. The heterocyclic
compounds bearing piperidine, pyrrolidine, morpholine, and
piperazine rings (4e–4h, respectively) exhibited increased solu-
bility in water; however, this had no effect on downregulated
lipid accumulation in macrophages. The double-head conju-
gated paeonol derivatives 5a and 5b were insoluble in water and
precipitated in media during cell-culture treatment.
Compounds 4i and 4j were similar structures bearing phenyl
rings with poor water solubility. Although 4j exhibited adequate
regulation of lipid accumulation at low doses, 4i caused cell
death. Similar phenomena were observed for compounds 4k
(cell death) and 4l (adequate regulation). Among the O-alkyl-
ation paeonol derivatives, compound 6a was the most potent
compound in inhibiting lipid accumulation. The piperidine- 10 Y. Q. Wang, M. Dai, J. C. Zhong and D. K. Yin, Biol. Pharm.
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phenylsulfonyl moieties bearing halide (7b, 7c, and 7d), OMe and S. Zheng, J. Gastroenterol. Hepatol., 2013, 28, 1223–1233.
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Conclusions
In summary, we synthesized 14 paeonol derivatives containing 17 C. H. Lau, C. M. Chan, Y. W. Chan, K. M. Lau, T. W. Lau,
Schiff-base conjugates and 11 O-alkylation derivatives. The
F. C. Lam, W. T. Law, C. T. Che, P. C. Leung, K. P. Fung,
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Y. Y. Ho and C. B. S. Lau, Phytomedicine, 2007, 14, 778–784.
results revealed that the compounds bearing a heterocyclic ring 18 H. Li, M. Dai and W. Jia, Planta Med., 2009, 75, 7–11.
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exerted no effect on downregulated lipid accumulation in
Pharmacol., 2010, 53, 169–176.
macrophages. The SAR analysis results indicated that 20 J. F. Zhao, S. J. J. Leu, S. K. Shyue, K. H. Su, J. Wei and
compounds 6a and 7a are potent inhibitors of lipid
T. S. Lee, Am. J. Chin. Med., 2013, 41, 1079–1096.
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RSC Adv., 2015, 5, 5652–5656 | 5655