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

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 app...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2020-05, Vol.25 (11), p.2518
Main Authors: Mahmoud, Sawsan, Samaha, Doaa, Mohamed, Mosaad S, Abou Taleb, Nageh A, Elsawy, Mohamed A, Nagamatsu, Tomohisa, Ali, Hamed I
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
antitumor
Apoptosis - drug effects
AutoDock
Cell Line, Tumor
deazaalloxazine
Drug Design
Drug Screening Assays, Antitumor
Flavins - chemistry
HeLa Cells
Humans
MCF-7 Cells
protein kinase
Protein-Tyrosine Kinases - metabolism
selectivity
Structure-Activity Relationship
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Summary: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 (IC : 0.17-2.17 µM) over HeLa tumor cell lines (IC > 100 µM). Protein kinase profiling revealed that compound 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 IC .
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules25112518