Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 7, Pages 2311-2319Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.02.005
Keywords
ABCB1; MDR; P-glycoprotein; Chalcones; GRIND
Funding
- Austrian Science Foundation [F3502, F3509]
- Higher Education Commission Pakistan
- Austrian Science Fund (FWF) [F 3502, F 3509] Funding Source: researchfish
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P-glycoprotein (P-gp) is an ATP-dependent multidrug resistance efflux transporter that plays an important role in anticancer drug resistance and in pharmacokinetics of medicines. Despite a large number of structurally and functionally diverse compounds, also flavonoids and chalcones have been reported as inhibitors of P-gp. The latter share some similarity with the well studied class of propafenones, but do not contain a basic nitrogen atom. Furthermore, due to their rigidity, they are suitable candidates for 3D-QSAR studies. In this study, a set of 22 new chalcone derivatives were synthesized and evaluated in a daunomycin efflux inhibition assay using the CCRF.CEM.VCR1000 cell line. The compound 10 showed the highest activity (IC50 = 42 nM), which is one order of magnitude higher than the activity for an equilipohillic propafenone analogue. 2D- and 3D-QSAR studies indicate the importance of H-bond acceptors, methoxy groups, hydrophobic groups as well as the number of rotatable bonds as pharmacophoric features influencing P-gp inhibitory activity. (c) 2014 Published by Elsevier Ltd.
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