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？μg/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 α,β-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
References
[1]
R. Krishna and L. D. Mayer, “Multidrug resistance (MDR) in cancerMechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs,” European Journal of Pharmaceutical Sciences, vol. 11, no. 4, pp. 265–283, 2000.
[2]
S. G. Aller, J. Yu, A. Ward et al., “Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding,” Science, vol. 323, no. 5922, pp. 1718–1722, 2009.
[3]
T. Bansal, M. Jaggi, R. K. Khar, and S. Talegaonkar, “Emerging significance of flavonoids as P-glycoprotein inhibitors in cancer chemotherapy,” Journal of Pharmacy & Pharmaceutical Sciences, vol. 12, no. 1, pp. 46–78, 2009.
[4]
D. I. Batovska and I. T. Todorova, “Trends in utilization of the pharmacological potential of chalcones,” Current Clinical Pharmacology, vol. 5, no. 1, pp. 1–29, 2010.
[5]
F. Bois, A. Boumendjel, A. M. Mariotte, G. Conseil, and A. Di Petro, “Synthesis and biological activity of 4-alkoxy chalcones: potential hydrophobic modulators of P-glycoprotein-mediated multidrug resistance,” Bioorganic and Medicinal Chemistry, vol. 7, no. 12, pp. 2691–2695, 1999.
[6]
F. Bois, C. Beney, A. Boumendjel, A. M. Mariotte, G. Conseil, and A. D. Pietro, “Halogenated chalcones with high-affinity binding to P-glycoprotein: potential modulators of multidrug resistance,” Journal of Medicinal Chemistry, vol. 41, no. 21, pp. 4161–4164, 1998.
[7]
X. L. Liu, H. W. Tee, and M. L. Go, “Functionalized chalcones as selective inhibitors of P-glycoprotein and breast cancer resistance protein,” Bioorganic and Medicinal Chemistry, vol. 16, no. 1, pp. 171–180, 2008.
[8]
A. Ivanova, D. Batovska, H. Engi et al., “MDR-reversal activity of chalcones,” In Vivo, vol. 22, no. 3, pp. 379–384, 2008.
[9]
Y. Han, M. Riwanto, M. L. Go, and P. L. R. Ee, “Modulation of breast cancer resistance protein (BCRP/ABCG2) by non-basic chalcone analogues,” European Journal of Pharmaceutical Sciences, vol. 35, no. 1-2, pp. 30–41, 2008.
[10]
F. L. Ansari, S. Nazir, H. Noureen, and B. Mirza, “Combinatorial synthesis and antibacterial evaluation of an indexed chalcone library,” Chemistry and Biodiversity, vol. 2, no. 12, pp. 1656–1664, 2005.
[11]
L. D. Chiaradia, R. dos Santos, C. E. Vitor et al., “Synthesis and pharmacological activity of chalcones derived from 2,4,6-trimethoxyacetophenone in RAW 264.7 cells stimulated by LPS: quantitative structure-activity relationships,” Bioorganic and Medicinal Chemistry, vol. 16, no. 2, pp. 658–667, 2008.
[12]
A. O. Oyedapo, V. O. Makanju, C. O. Adewunmi, E. O. Iwalewa, and T. K. Adenowo, “Antitrichomonal activity of 1,3-diaryl-2-propen-1-ones on Trichomonas gallinae,” African Journal of Traditional, Complementary and Alternative Medicines, vol. 1, no. 1, pp. 55–62, 2004.
[13]
C. O. Adewunmi, F. O. Ogungbamila, and J. O. Oluwadiya, “Molluscicidal activities of some synthetic chalcones,” Planta Medica, vol. 53, no. 1, pp. 110–112, 1987.
[14]
Advanced Technology & Industrial Co., Ltd., November 2010, http://www.advtechind.com/.
[15]
J. Rojas, J. N. Domínguez, J. E. Charris, G. Lobo, M. Payá, and M. L. Ferrándiz, “Synthesis and inhibitory activity of dimethylamino-chalcone derivatives on the induction of nitric oxide synthase,” European Journal of Medicinal Chemistry, vol. 37, no. 8, pp. 699–705, 2002.
[16]
M. M. Cornwell, I. Pastan, and M. M. Gottesman, “Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein,” Journal of Biological Chemistry, vol. 262, no. 5, pp. 2166–2170, 1987.
[17]
A. M. J. Frisch, G. W. Trucks, H. B. Schlegel, et al., Gaussian 98 Revision A.7, Gaussian, Inc., Pittsburgh, Pa, USA, 1998.
[18]
“Marvin, Calculator Plugin and Chemical Terms Demo,” July 2010, http://www.chemaxon.com/marvin/sketch/index.jsp.
[19]
D. Batovska, S. Parushev, A. Slavova et al., “Study on the substituents' effects of a series of synthetic chalcones against the yeast Candida albicans,” European Journal of Medicinal Chemistry, vol. 42, no. 1, pp. 87–92, 2007.
[20]
G. F. Ecker, T. Stockner, and P. Chiba, “Computational models for prediction of interactions with ABC-transporters,” Drug Discovery Today, vol. 13, no. 7-8, pp. 311–317, 2008.
[21]
E. Nicolle, A. Boumendjel, S. Macalou et al., “QSAR analysis and molecular modeling of ABCG2-specific inhibitors,” Advanced Drug Delivery Reviews, vol. 61, no. 1, pp. 34–46, 2009.
[22]
R. B. Wang, C. L. Kuo, L. L. Lien, and E. J. Lien, “Structure-activity relationship: analyses of P-glycoprotein substrates and inhibitors,” Journal of Clinical Pharmacy and Therapeutics, vol. 28, no. 3, pp. 203–228, 2003.
[23]
A. Seelig, “A general pattern for substrate recognition by P-glycoprotein,” European Journal of Biochemistry, vol. 251, no. 1-2, pp. 252–261, 1998.
[24]
R. Václavíková, A. Boumendjel, M. Ehrlichová, J. Ková？, and I. Gut, “Modulation of paclitaxel transport by flavonoid derivatives in human breast cancer cells. Is there a correlation between binding affinity to NBD of P-gp and modulation of transport?” Bioorganic and Medicinal Chemistry, vol. 14, no. 13, pp. 4519–4525, 2006.
[25]
Y. K. Rao, S. H. Fang, and Y. M. Tzeng, “Synthesis and biological evaluation of , , -trimethoxychalcone analogues as inhibitors of nitric oxide production and tumor cell proliferation,” Bioorganic and Medicinal Chemistry, vol. 17, no. 23, pp. 7909–7914, 2009.
[26]
M. L. Go, X. Wu, and X. L. Liu, “Chalcones: an update on cytotoxic and chemoprotective properties,” Current Medicinal Chemistry, vol. 12, no. 4, pp. 483–499, 2005.
