Design,synthesis and biological evaluation of benzamide and phenyltetrazole derivatives with amide and urea linkers as BCRP inhibitors |
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Authors: | Nehaben A Gujarati Leli Zeng Pranav Gupta Zhe-Sheng Chen Vijaya L Korlipara |
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Institution: | Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, United States |
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Abstract: | Breast cancer resistant protein (BCRP/ABCG2), a 72 kDa plasma membrane transporter protein is a member of ABC transporter superfamily. Increased expression of BCRP causes increased efflux and therefore, reduced intracellular accumulation of many unrelated chemotherapeutic agents leading to multidrug resistance (MDR). A series of 31 benzamide and phenyltetrazole derivatives with amide and urea linkers has been synthesized to serve as potential BCRP inhibitors in order to overcome BCRP-mediated MDR. The target derivatives were tested for their cytotoxicity and reversal effects in human non-small cell lung cancer cell line H460 and mitoxantrone resistant cell line H460/MX20 using the MTT assay. In the benzamide series, compounds 6 and 7 exhibited a fold resistance of 1.51 and 1.62, respectively at 10 µM concentration which is similar to that of FTC, a known BCRP inhibitor. Compounds 27 and 31 were the most potent analogues in the phenyltetrazole series with amide linker with a fold resistance of 1.39 and 1.32, respectively at 10 µM concentration. For the phenyltetrazole series with urea linker, 38 exhibited a fold resistance of 1.51 which is similar than that of FTC and is the most potent compound in this series. The target compounds did not exhibit reversal effect in P-gp overexpressing resistant cell line SW620/Ad300 suggesting that they are selective BCRP inhibitors. |
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Keywords: | ABCG2 BCRP inhibitors Multidrug resistance Benzamide and phenyltetrazole derivatives Cytotoxicity and reversal assay |
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