Structure-activity relationship study of novel 2-aminobenzofuran derivatives as P-glycoprotein inhibitors.
Treatment of cancer patients with chemotherapeutic drugs is often associated with the occurrence of tumors with a multidrug resistance (MDR). Furthermore, the relation between overexpression of P-glycoprotein (P-gp) and resistant cancers has been well established. In this study, novel 2-aminobenzofuran derivatives were synthesized and tested for their ability to modulate P-gp mediated multidrug resistance (MDR) in vitro. The most potent compound, 43, increased P-gp inhibitory activity at 5 μM by 11.12-fold and was 3.6-fold stronger than verapamil. Furthermore, 43 can sensitize Flp-In™-293/MDR cells toward vincristine, paclitaxel and doxorubicin by 17.95-fold, 13.68-fold and 26.43-fold at 2.5 μM, respectively. 43 also can sensitize the resistant cancer cell line KBvin toward vincristine, paclitaxel and doxorubicin by 246.43-fold, 38.72-fold and 5.16-fold at 2.5 μM, respectively. In conclusion, important aspects for developing potent P-gp inhibitors have been emphasized in this study, providing a starting point for the further structural optimization of P-gp inhibitors.
School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC.
Chien-Yu
CY
Chen
School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC; Department of Pharmacy, China Medical University Hospital, 2 Yude Road, Taichung 404, Taiwan, ROC.
Chin-Min
CM
Lin
School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC.
Hui-Chang
HC
Lin
Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan, ROC.
Chien-Fu
CF
Huang
School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC.
Chih-Yu
CY
Lee
School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC.
Tze-Chun
TC
Si Tou
School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC; Department of Pharmacy, China Medical University Hospital, 2 Yude Road, Taichung 404, Taiwan, ROC. Electronic address: cc0206hung@gmail.com.
Chin-Chuan
CC
Hung
School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC. Electronic address: chihshiang@mail.cmu.edu.tw.
Chih-Shiang
CS
Chang
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000586:Amination; D000970:Antineoplastic Agents / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014750:Vincristine / Q000494:pharmacology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D001572:Benzofurans; D014750:Vincristine; D004317:Doxorubicin; D017239:Paclitaxel
2-Aminobenzofuran; ABCB1; MDR; Multidrug resistance; P-glycoprotein; P-gp