Abstract
This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.
Highlights
We are living in an exciting era when research is being turned into real-world improvements in diagnosis, prevention, and therapy
Molecular docking studies were performed to investigate the affinity of the prepared compounds to Fms-like tyrosine kinase 3 (FLT3) kinase enzyme which was expressed in an interesting value in the above-mentioned target-affinity prediction
N-methyl piperazine instead of the primary amine compounds 7a and 7b led to an increase in activity specially for compound 7a which exhibited about 40% drop in cell viability at 10 μM in HT-29 and MCF-7 cell lines
Summary
We are living in an exciting era when research is being turned into real-world improvements in diagnosis, prevention, and therapy. Heterocyclic ring structures containing the thienopyrimidine moiety are of interest due to their varied pharmacological and biological properties [2,3,4] They are bio-isosteres to purine with a thiophene ring intertwined with pyrimidine. Most of the synthesized anticancer compounds have an heterocyclic core derivatized from pyrimidine, and many of them are thienopyrimidines They have recently been investigated as scaffolds for protein kinase (PKs) inhibitors [10,11,12,13,14,15,16]. Introduced thienopyrimidine as a core and different functional groups were incorporated at position 4 This derivatization is supported by recent reports of kinase inhibitors bearing thieno[2,3-d]pyrimidine fragments [13,14]. Compounds that showed the best results were subjected for their apoptosis /necrosis assessment using flow cytometric analysis
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