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Synthesis of 5‐Hydroxy‐3′,4′,7‐trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2‐Mediated Anticancer Drug Resistance
Author(s) -
Tsunekawa Ryuji,
Katayama Kazuhiro,
Hanaya Kengo,
Higashibayashi Shuhei,
Sugimoto Yoshikazu,
Sugai Takeshi
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800431
Subject(s) - abcg2 , chemistry , atp binding cassette transporter , multiple drug resistance , stereochemistry , p glycoprotein , flavones , efflux , pharmacology , biochemistry , transporter , biology , chromatography , gene , antibiotics
3′,4′,7‐Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP‐binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C‐5 and several kinds of capping moiety at the C‐7 hydroxy group, on the same 3′,4′‐dimethoxy‐substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP‐expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI 50 ). Of the synthesized compounds, the reversal effect of 5‐hydroxy‐3′,4′,7‐trimethoxyflavone (HTMF, RI 50 7.2 n m ) towards 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) was stronger than that of TMF (RI 50 18 n m ). Fluoro‐substituted 5‐fluoro‐3′,4′,7‐trimethoxyflavone (FTMF, RI 50 25 n m ) and monoglycosylated 7‐(β‐glucosyloxy)‐5‐hydroxy‐3′,4′‐dimethoxyflavone (GOHDMF, 91 n m ) also exhibited reversal effects, whereas the di‐ and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μ m upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μ m TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP‐mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.