Synthesis And Topoisomerases Inhibitory Activities Evaluation Of Quinoline Derivatives Containing ?,?-unsaturated Ketone Fragments

Human topoisomerase?Topo?has been recognized as an important target in anticancer drug discovery.Two types of topoisomerase exist in humans,namely,type I topoisomerase?Topo I?and type II topoisomerase?Topo II?.Both isomers are nuclear enzymes essential to resolve topological problems that occur during DNA transcription,replication,and chromosome segregation.Topo is the target for several commonly prescribed anticancer drugs,including etoposide,doxorubicin,and camptothecin.Since the identification of amsacrine as a Topo II-targeted anticancer drug in 1984,about 50%of current treatment protocols still employ at least one drug directed against topoisomerases.However,drug resistance and the severe side effects of Topo-targeted drugs are an issue.Novel and safer Topoisomerase inhibitors for better anticancer therapeutics are highly active research field.Quinoline is widely used in the drug design and discovery to develop bioactive molecules with various pharmacological activities,such as antimalarial,antibiotic,anticancer,and anti-inflammatory activities.Camptothecin,topotecan,irinotecan,belototecan and amsacrine are classical Topo inhibitors with the structures of quinoline rings.In addition,chalcone remained a fascination among researchers in the 21 Century due to its various pharmacological effects,including anticancer,antioxidant,anti-inflammatory,and anti-infective activity.Natural chalcone derivatives such as licochalcone A and isoliquiritigenin have excellent anticancer activities.In order to obtain novel anticancer drugs,a series of quinoline-chalcone derivatives were designed and synthesized via a pharmacophore hybridization strategy.In this study,we synthesized 30 quinoline-chalcone derivatives and 25 quinoline-rhodanine derivatives that containing?,?-unsaturated ketone.The structures of the target compounds were identified by ¹H-NMR,¹³C-NMR and MS spectra or HRMS spectra.The MTT and Topoisomerase inhibition assay were employed to study the activities of the newly synthesized compounds.The results suggest that quinoline-chalcone derivatives showed strong cytotoxicties against Hep G2,A549,LNCaP cancer cells line.The most potent compounds?₅,?₉ and?₉ showed excellent activity againt Hep G2 with an IC₅₀values of 0.60,0.53 and 0.23?mol·L^-1respectively.Quinoline-rhodanine derivatives compound 5i and 5l displayed potent Topo I inhibition activities at 20?mol·L^-1.This study will provide experimental basis and theoretical guidance for the development of quinoline derivatives as anticancer agents.