Breast cancer resistance protein (BCRP/ABCG2): new inhibitors and QSAR studies by a 3D linear solvation energy approach.
A series of compounds derived from naturally occurring flavonoids and synthetic analogs have been evaluated on cell lines overexpressing the wild-type breast cancer resistance protein (BCRP/ABCG2) half-transporter. Human ABCG2-transfected cells were used for screening their inhibitory activity. Five new natural compounds obtained from Morus mesozygia Stapf and one synthetic chromone, comprising a flavonoidic scaffold, were also evaluated. Based on the results obtained with a total of 34 compounds, a 3D linear solvation energy QSAR was investigated by VolSurf descriptors of molecular-interaction fields (MIFs) related to hydrophobic-interaction forces, polarisability and hydrogen-bonding capacity. Accuracy of the constructed 3D-QSAR model was attested by a correlation coefficient r(2) of 0.77. Shape parameters and hydrophobicity were revealed to be major physicochemical parameters responsible for the inhibition activity of flavonoid derivatives and synthetic analogs towards ABCG2, whereas hydrogen-bond donor capacity appeared highly unfavorable.
Nicolle
Edwige
E
Département de Pharmacochimie Moléculaire, UMR 5063, ICMG-FR 2607-Université Joseph Fourier Grenoble I, St Martin d'Hères, France.
Boccard
Julien
J
Guilet
David
D
Dijoux-Franca
Marie-Geneviève
MG
Zelefac
Fabien
F
Macalou
Sira
S
Grosselin
Jeanne
J
Schmidt
Julien
J
Carrupt
Pierre-Alain
PA
Di Pietro
Attilio
A
Boumendjel
Ahcène
A
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D016018:Least-Squares Analysis; D008942:Mitoxantrone / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D031625:Morus / Q000737:chemistry; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D024301:Plant Bark / Q000737:chemistry; D025341:Principal Component Analysis; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D013499:Surface Properties; D014162:Transfection
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005419:Flavonoids; D009363:Neoplasm Proteins; D008942:Mitoxantrone