Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/10974
Title: Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance : structure-activity relationships
Authors: Chan, KF
Zhao, Y
Chow, TWS
Yan, CSW
Ma, DL
Burkett, BA
Wong, ILK
Chow, LMC 
Chan, TH
Keywords: Flavonoid Dinners
Multidrug Resistance Paclitaxel
P-Glycoprotein
Structure-Activity Relationships
Issue Date: 2009
Publisher: Wiley-VCH
Source: ChemMedChem, 2009, v. 4, no. 4, p. 594-614 How to cite?
Journal: Chemmedchem 
Abstract: We 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 IC50 values 4 45-fold.
URI: http://hdl.handle.net/10397/10974
ISSN: 1860-7179
EISSN: 1860-7187
DOI: 10.1002/cmdc.200800413
Appears in Collections:Journal/Magazine Article

Access
View full-text via PolyU eLinks SFX Query
Show full item record

SCOPUSTM   
Citations

29
Last Week
0
Last month
0
Citations as of Dec 3, 2017

WEB OF SCIENCETM
Citations

28
Last Week
0
Last month
0
Citations as of Dec 9, 2017

Page view(s)

76
Last Week
0
Last month
Checked on Dec 11, 2017

Google ScholarTM

Check

Altmetric



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.