Abstract
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.
Highlights
Cancer is a severe health problem in the United States
We investigated the antitumor activities of 5-deazaflavins and flavins derivatives against a variety of cancer cell lines and elucidated that these candidates could be promising antitumor drugs [7,8]
The different amination reactions have been done by substitution of 2-methylthio group with different amines for preparation of 2-(substituted alkylamino), 2-(heterocyclic substituted)- and 2-amino-2-deoxo-5-deazaalloxazines {pyrimido[4,5-b]
Summary
Cancer is a severe health problem in the United States. 1.8 million new cases diagnosed with cancer and nearly 606,520 died from it in the US [1]. The selective PTK inhibitors are prospective candidates as antitumor agents by inhibiting multiple pathways in cancer cells, such as proliferation, survival and angiogenesis [2]. The synthesis of small molecules as PTK inhibitors (PTKIs) has developed into a remarkable approach toward new therapeutics [3]. After the Food and Drug Administration (FDA) approval for imatinib in Molecules 2020, 25, 2518; doi:10.3390/molecules25112518 www.mdpi.com/journal/molecules
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