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Article: Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: Structure-activity relationships

TitleFlavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: Structure-activity relationships
Authors
Issue Date2009
PublisherWiley - V C H Verlag GmbH & Co KGaA. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/110485305
Citation
Chemmedchem, 2009, v. 4 n. 4, p. 594-614 How to Cite?
AbstractWe recently described the modulatory activities of apigenin homodimers linked by ethylene glycol units in multidrug-resistant breast cancer and leukemic cells overexpressing ABCB1 (P-glycoprotein, P-gp). To further improve the potency of these dimers, a small library of flavonoid homodimers and hetero-dimers were synthesized, and their in vitro activity in reversing cellular resistance to paclitaxel, along with structure activity relationships (SAR), were evaluated using a P-gp-expressing human breast cancer cell line. Among these synthesized homodimers, many showed more potent reversing activity than that of the parent compound and verapamil. Two compounds in particular showed promising reversing activity at sub-micro-molar concentrations with no cytotoxic effects. Regarding SAR trends, flavonoid dimers with nonpolar and hydrophobic sub-stituents (e.g., methyl and ethyl groups) generally showed more potent resistance-reversing activity than that of dimers with polar and hydrophilic substituents (e.g. hydroxy groups) at the C3, C6, and C7 positions, but not at C5. In terms of sub-stituent steric bulk at C6, it was found that the flavonoid dimer with methyl groups was optimal, with bulkier substituents leading to lower reversing activity. Comparisons of flavonoid heterodimers with the corresponding homodimers revealed that the two binding sites on P-gp for flavonoid moieties are quite similar to each other. Besides paclitaxel, these new compounds also increased drug accumulation and enhanced the cytotoxicity of other cancer drugs such as doxorubicin, vincris-tine, and vinblastine by decreasing the IC 50 values 4 45-fold. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
Persistent Identifierhttp://hdl.handle.net/10722/168377
ISSN
2015 Impact Factor: 2.98
2015 SCImago Journal Rankings: 1.183
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChan, KFen_US
dc.contributor.authorZhao, Yen_US
dc.contributor.authorChow, TWSen_US
dc.contributor.authorYan, CSWen_US
dc.contributor.authorMa, DLen_US
dc.contributor.authorBurkett, BAen_US
dc.contributor.authorWong, ILKen_US
dc.contributor.authorChow, LMCen_US
dc.contributor.authorChan, THen_US
dc.date.accessioned2012-10-08T03:18:11Z-
dc.date.available2012-10-08T03:18:11Z-
dc.date.issued2009en_US
dc.identifier.citationChemmedchem, 2009, v. 4 n. 4, p. 594-614en_US
dc.identifier.issn1860-7179en_US
dc.identifier.urihttp://hdl.handle.net/10722/168377-
dc.description.abstractWe recently described the modulatory activities of apigenin homodimers linked by ethylene glycol units in multidrug-resistant breast cancer and leukemic cells overexpressing ABCB1 (P-glycoprotein, P-gp). To further improve the potency of these dimers, a small library of flavonoid homodimers and hetero-dimers were synthesized, and their in vitro activity in reversing cellular resistance to paclitaxel, along with structure activity relationships (SAR), were evaluated using a P-gp-expressing human breast cancer cell line. Among these synthesized homodimers, many showed more potent reversing activity than that of the parent compound and verapamil. Two compounds in particular showed promising reversing activity at sub-micro-molar concentrations with no cytotoxic effects. Regarding SAR trends, flavonoid dimers with nonpolar and hydrophobic sub-stituents (e.g., methyl and ethyl groups) generally showed more potent resistance-reversing activity than that of dimers with polar and hydrophilic substituents (e.g. hydroxy groups) at the C3, C6, and C7 positions, but not at C5. In terms of sub-stituent steric bulk at C6, it was found that the flavonoid dimer with methyl groups was optimal, with bulkier substituents leading to lower reversing activity. Comparisons of flavonoid heterodimers with the corresponding homodimers revealed that the two binding sites on P-gp for flavonoid moieties are quite similar to each other. Besides paclitaxel, these new compounds also increased drug accumulation and enhanced the cytotoxicity of other cancer drugs such as doxorubicin, vincris-tine, and vinblastine by decreasing the IC 50 values 4 45-fold. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.en_US
dc.languageengen_US
dc.publisherWiley - V C H Verlag GmbH & Co KGaA. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/110485305en_US
dc.relation.ispartofChemMedChemen_US
dc.subject.meshApigenin - Chemistryen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Survival - Drug Effectsen_US
dc.subject.meshDimerizationen_US
dc.subject.meshDrug Resistance, Multiple - Drug Effectsen_US
dc.subject.meshFlavonoids - Chemical Synthesis - Chemistry - Pharmacologyen_US
dc.subject.meshHumansen_US
dc.subject.meshMicrowavesen_US
dc.subject.meshMolecular Structureen_US
dc.subject.meshP-Glycoprotein - Chemistry - Metabolismen_US
dc.subject.meshPaclitaxel - Chemical Synthesis - Chemistry - Pharmacologyen_US
dc.subject.meshStructure-Activity Relationshipen_US
dc.titleFlavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: Structure-activity relationshipsen_US
dc.typeArticleen_US
dc.identifier.emailMa, DL:edmondma@hku.hken_US
dc.identifier.authorityMa, DL=rp00760en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1002/cmdc.200800413en_US
dc.identifier.pmid19288491-
dc.identifier.scopuseid_2-s2.0-65549092069en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-65549092069&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume4en_US
dc.identifier.issue4en_US
dc.identifier.spage594en_US
dc.identifier.epage614en_US
dc.identifier.isiWOS:000265797800013-
dc.publisher.placeGermanyen_US
dc.identifier.scopusauthoridChan, KF=16315233100en_US
dc.identifier.scopusauthoridZhao, Y=7406636675en_US
dc.identifier.scopusauthoridChow, TWS=26535649900en_US
dc.identifier.scopusauthoridYan, CSW=26641585600en_US
dc.identifier.scopusauthoridMa, DL=7402075538en_US
dc.identifier.scopusauthoridBurkett, BA=36802327300en_US
dc.identifier.scopusauthoridWong, ILK=7102513945en_US
dc.identifier.scopusauthoridChow, LMC=7202533071en_US
dc.identifier.scopusauthoridChan, TH=35291257900en_US

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