Design, semi-synthesis and examination of new gypsogenin derivatives against leukemia via Abl tyrosine kinase inhibition and apoptosis induction

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dc.authoridEMIRDAG, SAFIYE/0000-0002-1676-2881
dc.authoridSever, Belgin/0000-0003-4847-9711
dc.authorscopusid57211138682
dc.authorscopusid6503914739
dc.authorscopusid57211135955
dc.authorscopusid55797332300
dc.authorscopusid56624185800
dc.authorscopusid36905553700
dc.authorscopusid57916244400
dc.authorwosidSever, Belgin/V-8319-2017
dc.contributor.authorUlusoy, Nafia Gokce
dc.contributor.authorEmirdag, Safiye
dc.contributor.authorSozer, Ece
dc.contributor.authorRadwan, Mohamed O.
dc.contributor.authorCiftci, Halilibrahim
dc.contributor.authorAksel, Mehran
dc.contributor.authorOzmen, Ali
dc.date.accessioned2023-01-12T19:54:59Z
dc.date.available2023-01-12T19:54:59Z
dc.date.issued2022
dc.departmentN/A/Departmenten_US
dc.description.abstractChronic myelogenous leukemia (CML) is characterized by Philadelphia translocation arising from Bcr-Abl fusion gene, which encodes abnormal oncoprotein showing tyrosine kinase (TK) function. Certain mutations in kinase domain, off-target effects and resistance problems of current TK inhibitors require the discovery of novel Abl TK inhibitors. For this purpose, herein, we synthesized new gypsogenin derivatives (6a-l) and evaluated their anticancer effects towards CML cells along with healthy cell line and different leukemic cells. Among these compounds, compound 6l was found as the most active anti-leukemic agent against K562 CML cells compared to imatinib exerting less cytotoxicity towards PBMCs (healthy). This compound also revealed significant anti -leukemic effects against Jurkat cell line. Besides, compound 6l enhanced apoptosis in CML cells with 52.4 % when compared with imatinib (61.8 %) and inhibited Abl TK significantly with an IC50 value of 13.04 +/- 2.48 mu M in a large panel of kinases accentuating Abl TK-mediated apoptosis of compound 6l in CML cells. Molecular docking outcomes showed that compound 6l formed mainly crucial interactions in the ATP-binding cleft of Abl TK similar to that of imatinib. Ultimately, in silico pharmacokinetic evaluation of compound 6l indicated that this compound was endowed with anti-leukemic drug candidate features.en_US
dc.description.sponsorship2544 Scientific and Technological Research Institution of Turkey (TUBITAK); Japan Society for the Promotion of Science (JSPS) Bilateral Cooperation Project [117R034]; TUBITAK 2236 CoCirculation2 [121C063]; TUBITAKen_US
dc.description.sponsorshipThis study was supported by 2544 Scientific and Technological Research Institution of Turkey (TUBITAK) and Japan Society for the Promotion of Science (JSPS) Bilateral Cooperation Project (No. 117R034). This publication has been produced benefiting from TUBITAK 2236 CoCirculation2, grant number 121C063. However, the entire responsibility of the publication belongs to the authors. The financial support received from TUBITAK does not mean that the content of the publication is approved in a scientific sense by TUBITAK.en_US
dc.identifier.doi10.1016/j.ijbiomac.2022.09.257
dc.identifier.endpage1499en_US
dc.identifier.issn0141-8130
dc.identifier.issn1879-0003
dc.identifier.pmid36195231en_US
dc.identifier.scopus2-s2.0-85139361496en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1487en_US
dc.identifier.urihttps://doi.org/10.1016/j.ijbiomac.2022.09.257
dc.identifier.urihttps://hdl.handle.net/11454/76584
dc.identifier.volume222en_US
dc.identifier.wosWOS:000876829000004en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.ispartofInternational Journal of Biological Macromoleculesen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectChronic myelogenous leukemiaen_US
dc.subjectAbl tyrosine kinaseen_US
dc.subjectApoptosisen_US
dc.subjectGypsogenin derivativesen_US
dc.subjectImatiniben_US
dc.subjectMolecular dockingen_US
dc.subjectChronic Myelogenous Leukemiaen_US
dc.subjectBcr-Ablen_US
dc.subjectTriterpenoid Saponinsen_US
dc.subjectReductive Aminationen_US
dc.subjectIn-Vitroen_US
dc.subjectResistanceen_US
dc.subjectImatiniben_US
dc.subjectKetonesen_US
dc.subjectRootsen_US
dc.subjectCellsen_US
dc.titleDesign, semi-synthesis and examination of new gypsogenin derivatives against leukemia via Abl tyrosine kinase inhibition and apoptosis inductionen_US
dc.typeArticleen_US

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