Abstract

The synthesis of a novel library of 8-arylated quercetin derivatives bearing phenolic hydroxyl group applying Suzuki-Miyaura cross-coupling reaction between 8-iodoquercetin methyl ether and various methoxyl and / or fluorine substituted aryl boronic acids is reported. Corresponding 8-arylated quercetin derivatives were synthesized in a five-step reaction sequence consisting of acid hydrolysis of commercially cheap rutin, followed by O -methylation of the obtained quercetin with dimethyl sulfate. After iodination of quercetin methyl ether with N-Iodosuccinimide (NIS), the resulting 8-iodoquercetin proved to be effective electrophile in reactions with various methoxyl and/or fluorine substituted aryl boronic acids. Finally, the 8-arylated permethylated quercetin ethers underwent de-methylation to provide polyphenolic derivatives. The obtained quercetin derivatives were well characterized by the 1 H NMR, 13 C NMR and HRMS data. Preliminary biological evaluations showed that some of the synthesized 8-arylated quercetin derivatives possessed very high anti-cancer cell proliferation activity in MGC-803 and OVCAR-3 cancer cell lines (IC 50 < 5.0 µmol/L) as well as high activity in HCC827 cancer cell line (IC 50 <10 µmol/L) in vitro . Among these compounds, compound 5h with para -fluorine and ortho -methoxyl substitution exhibited best activity against MGC-803 and HCC827 (IC 50  = 2.91 µmol/L, 9.42 µmol/L), respectively. while compound 6g with meta -fluorine and para -hydroxyl substitution showed best activity aganist OVCAR-3 cells (IC 50  = 3.88 µmol/L). Furthermore, the 1,1-diphenyl-2-methylbenzohydrazine (DPPH) scavenging experiment showed all compounds exhibited better antioxidant activity than quercetin, in particular quercetin derivative 6f containing para -hydroxyl and meta -hydroxyl substitution. The disclosed structure-activity relationship also offers new examples for application of fluorine modifications as versatile tools in drug discovery.