title: 2-Trifluoromethyl-2-Hydroxypropionamide Derivatives as Novel Reversal Agents of ABCG2 (BCRP)-Mediated Multidrug Resistance: Synthesis and Biological Evaluations.
abstract: It has been postulated that one of the biggest impediments to a successful chemotherapy is the phenomena of multidrug resistance (MDR) in cancer cells. One of the main mechanisms of MDR is overexpression of the ATP-binding cassette (ABC) transporters in cancer cells which alters absorption, distribution, metabolism, and excretion of various chemotherapeutic drugs. Efforts have been made to find effective inhibitors of ABC transporters. However, none has been approved clinically. This study shows that a novel compound 3-chloro-N-(2-hydroxyphenyl)-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropanamido) benzamide (compound 7d), one of the 2-trifluoromethyl-2-hydroxypropionamide derivatives could reverse ABCG2 (BCRP)-mediated MDR. Cytotoxicity studies show that compound 7d sensitizes the ABCG2-overexpressing cells to chemotherapeutic drugs mitoxantrone and SN-38, which are well-established substrates of the ABCG2 transporter. Western blotting results indicate that compound 7d does not significantly alter the protein level of the ABCG2 transporter. Accumulation and efflux studies demonstrate that compound 7d increases intracellular accumulation of mitoxantrone by inhibiting the function of ABCG2. Overall, these findings indicate a potential use for compound 7d as an adjuvant agent for chemotherapy to inhibit the function of the clinically relevant ABC transporter and sensitize tumor cells to chemotherapeutic drugs. J. Cell. Biochem. 118: 2420-2429, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy Health Sciences, St. John's University, Queens, New York.
authors.forename: Rishil J
authors.initials: RJ
authors.lastname: Kathawala
authors.affiliation: Key laboratory of Bioorganic Phosphorus and Chemical Biology, The Ministry of Education, Department of Chemistry, Tsinghua University, Beijing, China.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy Health Sciences, St. John's University, Queens, New York.|Laboratory of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Danwen
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Thoracic Surgery, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Hui-Qin
authors.initials: HQ
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy Health Sciences, St. John's University, Queens, New York.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Laboratory of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key laboratory of Bioorganic Phosphorus and Chemical Biology, The Ministry of Education, Department of Chemistry, Tsinghua University, Beijing, China.
authors.forename: Changmei
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy Health Sciences, St. John's University, Queens, New York.
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D000077146:Irinotecan; D008942:Mitoxantrone / Q000494:pharmacology
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001549:Benzamides; C037689:benzamide; D000077146:Irinotecan; D008942:Mitoxantrone; D002166:Camptothecin
keywords: 2-TRIﬂUOROMETHYL-2-HYDROXYPROPIONAMIDE; ABC TRANSPORTER; ABCG2; MULTIDRUG RESISTANCE