Expeditious assembly of N-heteroaryl substituted quercetin derivatives as potent anticancer agents.

• Facile assembly of a small library of N-heteroarylated quercetin derivatives via Suzuki-Miyaura reaction are realized • 28 N-heteroarylated quercetin derivatives were tested against 3 types of human cancer cell lines (MGC-803, HCC827, and OVCAR-3) in vitro • quinolin-7-yl substituted compound 2m exhibited best activity (IC 50 = 3.20 µmol/L) against HCC827 cancer cell lines at µmol/L level • The preliminary structure-activity relationship of pyridyl and quinolinyl substituted quercetin was disclosed. The synthesis of a small library of N -heteroaryl substituted quercetin derivatives (28 compounds) at the C8 position applying Suzuki-Miyaura cross-coupling reaction between 8-iodoquercetin methyl ether and various pyridylboronic acids or quinolylboronic acids is reported. The obtained quercetin derivatives 2a - 2n and 3a - 3n were well characterized by the 1H NMR, 13C NMR and HRMS data. Preliminary biological evaluations showed that some of the synthesized 8-heteroarylated quercetin derivatives possessed very high anti-cancer cell proliferation activity in HCC827 cancer cell line (IC 50 < 5.0 µmol/L) in vitro. Among these synthesized compounds, quinolin-7-yl substituted compound 2m exhibited best activity in HCC827 (IC 50 = 3.20 µmol/L), while quinolin-3-yl substituted compound 2i showed best activity in MGC-803 cells (IC 50 = 14.92 µmol/L). The 3-pyridyl compound 3c with ortho -fluorine showed best activity in OVCAR-3 cells (IC 50 = 10.67 µmol/L). The disclosed structure-activity relationship provides hints that large steric hindrance at the C8 position of quercetin alter the anticancer activities and also offers new examples for new application of electronic and steric modifications as versatile tools in drug discovery. The synthesis of a small library of N -heteroaryl substituted quercetin derivatives (28 compounds) at the C8 position applying Suzuki-Miyaura cross-coupling reaction between 8-iodoquercetin methyl ether and various pyridylboronic acids or quinolylboronic acids is reported. The obtained quercetin derivatives 2a - 2n and 3a - 3n were well characterized by the 1H NMR, 13C NMR and HRMS data. Preliminary biological evaluations showed that some of the synthesized 8-heteroarylated quercetin derivatives possessed very high anti-cancer cell proliferation activity in HCC827 cancer cell line (IC 50 < 5.0 µmol/L) in vitro. Among these synthesized compounds, quinolin-7-yl substituted compound 2m exhibited best activity in HCC827 (IC 50 = 3.20 µmol/L), while quinolin-3-yl substituted compound 2i showed best activity in MGC-803 cells (IC 50 = 14.92 µmol/L). The 3-pyridyl compound 3c with ortho -fluorine showed best activity in OVCAR-3 cells (IC 50 = 10.67 µmol/L). The disclosed structure-activity relationship provides hints that large steric hindrance at the C8 position of quercetin alter the anticancer activities and also offers new examples for new application of electronic and steric modifications as versatile tools in drug discovery. [Display omitted] [ABSTRACT FROM AUTHOR]