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Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells.
Cancer Chemother Pharmacol. 2009 May; 63(6):1007-16.CC

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 IC(50) values ranging from 21.69 to 197 microM. 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 IC(50) values are 30.81, 39.29 and 71.17 microM, respectively. Chromones, isoflavones, flavanones and coumarins showed much lower potencies when compared to the first two groups with IC(50) ranges of 61 to >400, 131 to >400, 138 to >400 and 360.85 to >400 microM, 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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Loa J
Department of Experimental Surgery, Singapore General Hospital, BLK 9, Level 3, Outram Road, Singapore, 169608, Singapore.
Chow P
No affiliation info available
Zhang K
No affiliation info available

MeSH

Antineoplastic AgentsApoptosisCell CycleCell Line, TumorChalconesFlavonoidsHumansInhibitory Concentration 50Liver NeoplasmsMolecular StructurePhenolsPlant ExtractsPolyphenolsStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18766342

Citation

Loa, Jacky, et al. "Studies of Structure-activity Relationship On Plant Polyphenol-induced Suppression of Human Liver Cancer Cells." Cancer Chemotherapy and Pharmacology, vol. 63, no. 6, 2009, pp. 1007-16.
Loa J, Chow P, Zhang K. Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells. Cancer Chemother Pharmacol. 2009;63(6):1007-16.
Loa, J., Chow, P., & Zhang, K. (2009). Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells. Cancer Chemotherapy and Pharmacology, 63(6), 1007-16. https://doi.org/10.1007/s00280-008-0802-y
Loa J, Chow P, Zhang K. Studies of Structure-activity Relationship On Plant Polyphenol-induced Suppression of Human Liver Cancer Cells. Cancer Chemother Pharmacol. 2009;63(6):1007-16. PubMed PMID: 18766342.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells. AU - Loa,Jacky, AU - Chow,Pierce, AU - Zhang,Kai, Y1 - 2008/09/03/ PY - 2008/03/23/received PY - 2008/07/10/accepted PY - 2008/9/4/pubmed PY - 2009/4/18/medline PY - 2008/9/4/entrez SP - 1007 EP - 16 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother Pharmacol VL - 63 IS - 6 N2 - 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 IC(50) values ranging from 21.69 to 197 microM. 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 IC(50) values are 30.81, 39.29 and 71.17 microM, respectively. Chromones, isoflavones, flavanones and coumarins showed much lower potencies when compared to the first two groups with IC(50) ranges of 61 to >400, 131 to >400, 138 to >400 and 360.85 to >400 microM, 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. SN - 1432-0843 UR - https://www.unboundmedicine.com/medline/citation/18766342/Studies_of_structure_activity_relationship_on_plant_polyphenol_induced_suppression_of_human_liver_cancer_cells_ L2 - https://dx.doi.org/10.1007/s00280-008-0802-y DB - PRIME DP - Unbound Medicine ER -