Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

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dc.citation.epage122en_US
dc.citation.spage105en_US
dc.citation.volumeNumber103en_US
dc.contributor.authorVojtičková, M.en_US
dc.contributor.authorDobiaš J.en_US
dc.contributor.authorHanquet G.en_US
dc.contributor.authorAddová G.en_US
dc.contributor.authorCetin-Atalay, R.en_US
dc.contributor.authorYildirim, D.C.en_US
dc.contributor.authorBoháč, A.en_US
dc.date.accessioned2016-02-08T11:03:52Z
dc.date.available2016-02-08T11:03:52Z
dc.date.issued2015en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractStructure novelty, chemical stability and synthetic feasibility attracted us to design 1,2,3-triazole compounds as potential inhibitors of VEGFR2 tyrosine kinase. Novel triazoles T1-T7 were proposed by oxazole (AAZ from PDB: 1Y6A)/1,2,3-triazole isosteric replacement, molecular modelling and docking. In order to enable synthesis of T1-T7 we developed a methodology for preparation of ynamide 22. Compound 22 was used for all Click chemistry reactions leading to triazoles T1-T3 and T6-T7. Among the obtained products, T1, T3 and T7 specifically bind VEGFR2 TK and modulate its activity by concentration dependent manner. Moreover predicted binding poses of T1-T7 in VEGFR2 TK were similar to the one known for the oxazole inhibitor AAZ (PDB: 1Y6A). Unfortunately the VEGFR2 inhibition by triazoles e.g. T3 and T7 is lower than that determined for their oxazole bioisosters T3-ox and AAZ, resp. Different electronic properties of 1,2,3-triazole/oxazole heterocyclic rings were proposed to be the main reason for the diminished affinity of T1-T3, T6 and T7 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1-T3 and T6 were screened on cytotoxic activity against two human hepatocellular carcinoma cell lines. Selective cytotoxic activity of T2 against aggressive Mahlavu cells has been discovered indicating possible affinity of T2 to Mahlavu constitutionally active PI3K/Akt pathway. © 2015 Elsevier Masson SAS.en_US
dc.description.provenanceMade available in DSpace on 2016-02-08T11:03:52Z (GMT). No. of bitstreams: 1 bilkent-research-paper.pdf: 70227 bytes, checksum: 26e812c6f5156f83f0e77b261a471b5a (MD5) Previous issue date: 2015en
dc.identifier.doi10.1016/j.ejmech.2015.08.012en_US
dc.identifier.issn2235234
dc.identifier.urihttp://hdl.handle.net/11693/26718
dc.language.isoEnglishen_US
dc.publisherElsevier Masson SASen_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/j.ejmech.2015.08.012en_US
dc.source.titleEuropean Journal of Medicinal Chemistryen_US
dc.subjectCuACC Click chemistryen_US
dc.subjectCytotoxic activity in Huh-7 and Mahlavuen_US
dc.subjecthepatocellular carcinoma cell linesen_US
dc.subjectOxazole/1,2,3-triazole isosteric replacementen_US
dc.subjectPI3K/Akt pathwayen_US
dc.subjectVEGFR2 tyrosine kinase inhibitionen_US
dc.subjectYnamideen_US
dc.subject1,2,3 triazole derivativeen_US
dc.subject4 [4 [5 (ethylsulfonyl) 2 methoxyphenylamino] 1h 1,2,3 triazol 1 yl] 2 (pyridin 2 yl)phenolen_US
dc.subjectoxazoleen_US
dc.subjectphosphatidylinositol 3 kinaseen_US
dc.subjectprotein kinase Ben_US
dc.subjectprotein tyrosine kinase inhibitoren_US
dc.subjectunclassified drugen_US
dc.subjectvasculotropin receptor 2en_US
dc.subjectArticleen_US
dc.subjectbinding siteen_US
dc.subjectcarcinoma cell lineen_US
dc.subjectchemical reactionen_US
dc.subjectclick chemistryen_US
dc.subjectconcentration responseen_US
dc.subjectcontrolled studyen_US
dc.subjectcytotoxicityen_US
dc.subjectdrug structureen_US
dc.subjectdrug synthesisen_US
dc.subjectenzyme activityen_US
dc.subjecthumanen_US
dc.subjecthuman cellen_US
dc.subjectliver cell carcinomaen_US
dc.subjectmolecular dockingen_US
dc.subjectmolecular modelen_US
dc.titleYnamide Click chemistry in development of triazole VEGFR2 TK modulatorsen_US
dc.typeArticleen_US

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