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dc.contributor.authorLien, Vegard Torp
dc.contributor.authorPettersen, Solveig
dc.contributor.authorHaugen, Mads Haugland
dc.contributor.authorOlberg, Dag Erlend
dc.contributor.authorMælandsmo, Gunhild Mari
dc.contributor.authorKlaveness, Jo
dc.date.accessioned2020-03-09T13:42:34Z
dc.date.available2020-03-09T13:42:34Z
dc.date.issued2019-08-15
dc.description.abstractBased on the cabozantinib scaffold, novel c‐Met inhibitors were rationalized from the limited knowledge of structure‐activity relationships for the quinoline 6‐position. Emphasis was given to modifications capable of engaging in additional polar interactions with the c‐Met active site. In addition, <i>ortho</i>‐fluorinations of the terminal benzene ring were explored. Fifteen new molecules were synthesized and evaluated in a c‐Met enzymatic binding assay. A wide range of substituents were tolerated in the quinoline 6‐position, while the <i>ortho</i>‐fluorinations performed were shown to give considerable reductions in the c‐Met binding affinity. The antiproliferative effects of the compounds were evaluated in the NCI60 cancer cell line panel. Most notably, compounds 15b and 18b were able to inhibit cell proliferation more efficiently than cabozantinib in leukemia, CNS, and breast cancer cell lines. The in vitro data agreed well with the in silico docking results, where additional hydrogen bonding was identified in the enzymatic pocket for the <i>para</i>‐amino substituted 15b and 18b.en_US
dc.identifier.citationLien VT, Pettersen S, Haugen MH, Olberg DE, Mælandsmo GM, Klaveness J. Design, synthesis and biological evaluation of 6‐substituted quinolines derived from cabozantinib as c‐Met inhibitors. Archiv der Pharmazie. 2019;352(9)en_US
dc.identifier.cristinIDFRIDAID 1720828
dc.identifier.doi10.1002/ardp.201900101
dc.identifier.issn0365-6233
dc.identifier.issn1521-4184
dc.identifier.urihttps://hdl.handle.net/10037/17682
dc.language.isoengen_US
dc.publisherWileyen_US
dc.relation.journalArchiv der Pharmazie
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2019 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700en_US
dc.subjectVDP::Medisinske Fag: 700en_US
dc.titleDesign, synthesis and biological evaluation of 6‐substituted quinolines derived from cabozantinib as c‐Met inhibitorsen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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