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Article

Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs

1
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Helwan 11795, Egypt
2
Institute of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
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Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Helwan 11795, Egypt
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School of Pharmacy, Queen’s University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
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Leicester Institute of Pharmaceutical Innovation, Leicester School of Pharmacy, De Monfort University, The Gateway, Leicester LE1 9BH, UK
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Department of Medical Technology, Faculty of Health Science, Kumamoto Health Science University, Kumamoto 861-5598, Japan
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Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Kingsville, TX 78363, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Maria Cristina De Rosa
Molecules 2020, 25(11), 2518; https://doi.org/10.3390/molecules25112518
Received: 26 April 2020 / Revised: 20 May 2020 / Accepted: 25 May 2020 / Published: 28 May 2020
(This article belongs to the Special Issue Drug Discovery and Molecular Docking)
Protein 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 5-deazaalloxazine analogs into c-kit PTK (PDB code: 1t46) revealed reasonable correlations between their AutoDock binding free energy and IC50. View Full-Text
Keywords: deazaalloxazine; antitumor; AutoDock; selectivity; protein kinase deazaalloxazine; antitumor; AutoDock; selectivity; protein kinase
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MDPI and ACS Style

Mahmoud, S.; Samaha, D.; Mohamed, M.S.; Abou Taleb, N.A.; Elsawy, M.A.; Nagamatsu, T.; Ali, H.I. Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs. Molecules 2020, 25, 2518. https://doi.org/10.3390/molecules25112518

AMA Style

Mahmoud S, Samaha D, Mohamed MS, Abou Taleb NA, Elsawy MA, Nagamatsu T, Ali HI. Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs. Molecules. 2020; 25(11):2518. https://doi.org/10.3390/molecules25112518

Chicago/Turabian Style

Mahmoud, Sawsan, Doaa Samaha, Mosaad S. Mohamed, Nageh A. Abou Taleb, Mohamed A. Elsawy, Tomohisa Nagamatsu, and Hamed I. Ali 2020. "Design, Synthesis, Antitumor Activity and Molecular Docking Study of Novel 5-Deazaalloxazine Analogs" Molecules 25, no. 11: 2518. https://doi.org/10.3390/molecules25112518

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