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Studies of structure–activity relationship on plant polyphenol-induced suppression of human liver cancer cells

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Abstract

Purpose

To study anticancer activities of 68 plant polyphenols with different backbone structures and various substitutions and to analyze the structure–activity relationships.

Methods

Antiproliferative activity of 68 plant polyphenols on human liver cancer cells were screened by the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide method. Structure–activity relationships were analyzed by comparison of their activities with selected structures. Cell cycle progression was assayed by flow cytometry analysis and apoptosis was analyzed by DNA fragment assay.

Results

Based on their backbone structures, 68 polyphenols were sub-classed to flavonoids (chalcones, flavanones, flavones and isoflavones), chromones and coumarins. The order of their potency to suppress the human liver cancer cells is chalcones > flavones > chromones > isoflavones > flavanones > coumarins. Chalcones comprise the most potent group with IC50 values ranging from 21.69 to 197 µM. Top nine most potent chalcones in the group have hydroxylation at 2′-carbon position in B-ring. Flavones ranked second in their potencies. Quercetin, 4-hydroxyflavone and luteolin are three hydroxyflavones with highest potencies in this group. Their IC50 values are 30.81, 39.29 and 71.17 µM, respectively. Chromones, isoflavones, flavanones and coumarins showed much lower potencies when compared to the first two groups with IC50 ranges of 61 to >400, 131 to >400, 138 to >400 and 360.85 to >400 µM, respectively. In mechanistic studies, the most potent chalcone, 2,2′-dihydroxychalcone could induce G2/M arrest and then apoptosis of the cancer cells.

Conclusions

An analysis of structure–activity relationship showed that following structures are required for their inhibitory potencies on human liver cancer cells: (1) of the six sub-classes of the polyphenols tested, the unique backbone structure of chalcones with a open C-ring; (2) within the chalcone group, hydroxyl substitution at 2′-carbon of B-ring; (3) hydroxyl substitution at 3′-carbon in B-ring of flavones. However, some other structures were found to decrease their potencies: e.g. substitutions by sugar moieties in flavones. These data are valuable for design and modification of new polyphenols, which could be potential antiproliferative agents of cancer cells.

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Acknowledgments

This work is supported by research grants from National Medical Research Council of Singapore (NMRC/0985/2005 and NMRC/1029/2006). We are grateful to staff in Melbourne University for their support for attachment of Jacky Loa in our Lab. The authors also like to thank the staff in Department of Experimental Surgery, Singapore General Hospital, for their support and assistance.

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Authors and Affiliations

  1. Department of Experimental Surgery, Singapore General Hospital, BLK 9, Level 3, Outram Road, Singapore, 169608, Singapore

    Jacky Loa, Pierce Chow & Kai Zhang

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  1. Jacky Loa
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  2. Pierce Chow
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  3. Kai Zhang
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Correspondence to Kai Zhang.

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Loa, J., Chow, P. & Zhang, K. Studies of structure–activity relationship on plant polyphenol-induced suppression of human liver cancer cells. Cancer Chemother Pharmacol 63, 1007–1016 (2009). https://doi.org/10.1007/s00280-008-0802-y

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  • DOI: https://doi.org/10.1007/s00280-008-0802-y

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