%0 Journal Article
%T Comparative Study on the MDR Reversal Effects of Selected Chalcones
%A A. B. Ivanova
%A D. I. Batovska
%A I. T. Todorova
%A B. A. Stamboliyska
%A J. Serly
%A J. Molnar
%J International Journal of Medicinal Chemistry
%D 2011
%I Hindawi Publishing Corporation
%R 10.1155/2011/530780
%X Based on the structure of three previously established lead compounds, fifteen selected chalcones were synthesized and evaluated for their multidrug resistance (MDR) reversal activity on mouse lymphoma cells. The most active chalcones were stronger revertants than the positive control, verapamil. In the model of combination chemotherapy, the interactions between the anticancer drug doxorubicin and two of the most effective compounds were measured in vitro, on human MDR1 gene transfected mouse lymphoma cells, showing that the type of interaction for one of these compounds was indifferent while that for the other one was additive. Furthermore, two chalcones inhibited 50% of cell proliferation in concentration of around 0.4£¿¦Ìg/mL and were from 2- to 100-fold more active than the most chalcones. The structure-activity relationships were obtained and discussed in view of their usefulness for the design of chalcone-like P-gp modulators and drugs able to treat resistant cancers. 1. Introduction Multidrug resistance (MDR) against anticancer drugs is one of the major obstacles to successful chemotherapy. It refers to the ability of tumors to develop resistance to a number of structurally and functionally unrelated chemotherapeutic agents [1]. In malignant cells, MDR is predominantly mediated by the overexpression of P-glycoprotein (P-gp), which is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily. P-gp recognizes a wide range of compounds including anticancer drugs and actively transports them out of the cells thereby lowering their intracellular concentrations and pharmacological effects [2]. For this reason, developing inhibitors of P-gp-mediated drug efflux is of potential clinical value. Up to now a great variety of P-gp inhibitors has been discovered. Amongst them, flavonoids constitute the third generation, a nonpharmaceutical category of revertants. The effects produced by some of these components are found to be comparable to those of the well-known P-gp inhibitors verapamil and cyclosporine [3]. Within the last decade, interest intensified in the flavonoid subclass of chalcones. Chalcones (1,3-diarylprop-2-en-1-ones) are open-chain flavonoids consisting of two aromatic rings (A and B) that are joined by a three-carbon ¦Á,¦Â-unsaturated carbonyl system. They display a wide pharmacological spectrum including the dual effects of anticancer and MDR reversal activities, which makes them promising agents for cancer chemotherapy [4]. Chalcones are supposed to overlap two binding sites of the nucleotide-binding domain (NBD2) of P-gp
%U http://www.hindawi.com/journals/ijmc/2011/530780/