Design, synthesis, antitumor activity and molecular docking study of novel 5-deazaalloxazine analogs

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dc.cclicenceCC-BYen
dc.contributor.authorMahmoud, S.
dc.contributor.authorSamaha, D.
dc.contributor.authorMohamed, M.
dc.contributor.authorAbou Taleb, N.
dc.contributor.authorElsawy, M.
dc.contributor.authorNagamatsu, T.
dc.contributor.authorAli, H.
dc.date.acceptance2020-05-25
dc.date.accessioned2020-06-02T08:36:28Z
dc.date.available2020-06-02T08:36:28Z
dc.date.issued2020-05-28
dc.descriptionopen access articleen
dc.description.abstractProtein tyrosine kinases (PTKs) are the most potential therapeutic targets for cancer. Herein, we present a sound rationale for synthesis of a series of novel 2-(methylthio), 2-(substituted alkylamino), 2-(heterocyclic substituted), 2-amino, 2,4-dioxo and 2-deoxo-5-deazaalloxazine derivatives by applying structure-based drug design (SBDD) using AutoDock 4.2. Their antitumor activities against human CCRF-HSB-2, KB, MCF-7 and HeLa have been investigated in vitro. Many 5-deazaalloxazine analogs revealed high selective activities against MCF-7 tumor cell lines (IC50: 0.17–2.17 µM) over HeLa tumor cell lines (IC50 > 100 µM). Protein kinase profiling revealed that compound 3h induced multi- targets kinase inhibition including −43% against (FAK), −40% against (CDKI) and −36% against (SCR). Moreover, the Annexin-V/PI apoptotic assay elucidate that compound 3h showed 33% and potentially 140% increase in early and late apoptosis to MCF-7 cells respectively, compared to the control. The structure-activity relationship (SAR) and molecular docking study using PTK as a target enzyme for the synthesized 7-deazaalloaxazine derivatives were investigated as potential antitumor agents. The AutoDock binding affinities of the 5deazaalloxazine analogs into c-kit PTK (PDB code: 1t46) revealed reasonable correlations between their AutoDock binding free energy and IC50.en
dc.funderNo external funderen
dc.funder.otherStartup fund by Texas A&M Health Sciences Center (to H.I.A.; grant number: 121500-35558)en
dc.funder.otherJohn A. King foundation Ph.D. studentship, School of Pharmacy, Queen’s University of Belfasten
dc.identifier.citationMahmoud S., Samaha D., Mohamed M., Abou Taleb N., Elsawy M., Nagamatsu T., Ali H. (2020) Design, synthesis, antitumor activity and molecular docking study of novel 5-deazaalloxazine analogs. Molecules, 25: pp. 2518-2544en
dc.identifier.doihttps://doi.org/10.3390/molecules25112518
dc.identifier.urihttps://dora.dmu.ac.uk/handle/2086/19679
dc.language.isoen_USen
dc.peerreviewedYesen
dc.publisherMDPIen
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en
dc.titleDesign, synthesis, antitumor activity and molecular docking study of novel 5-deazaalloxazine analogsen
dc.typeArticleen

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