article · Bioorganic Chemistry
Fifteen novel thieno[2,3-d]pyrimidine derivatives were developed and evaluated for anticancer activity. Initial screening demonstrated that compounds 5f-i and 7a significantly impeded the proliferation of MDA-MB-468 breast cancer cells. These molecules also exhibited a better safety profile in normal WI-38 cells compared to the reference compound staurosporine. When evaluated against epidermal growth factor receptor (EGFR) kinase, derivatives 5g and 7a achieved potent two-digit nanomolar inhibition relative to erlotinib. Further investigation of the most active derivative, 5g, established that it arrests the cell cycle and triggers programmed cell death in MDA-MB-468 cells, accompanied by the detection of key apoptosis markers including Bax, Bcl-2, Caspase-8, and Caspase-9. Molecular docking and dynamic simulations accounted for the biological activity observed in the leading compound.
Identifying therapies that selectively target cancer cells while minimising harm to healthy cells remains a central challenge in oncology. By combining strong inhibition of EGFR kinase with lower toxicity toward normal cells in laboratory models, these compounds provide prospective chemical starting points for developing targeted anticancer therapies with improved safety margins.
This work represents early-stage drug discovery. The findings could interest oncology drug discovery teams seeking lead compounds for EGFR-driven cancers, particularly breast cancer. Extensive further preclinical development, including in vivo efficacy testing, toxicology, and pharmacokinetic optimisation, will be essential before these molecules could advance toward clinical trials or commercial pharmaceutical applications.
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The current study discovered fifteen new thieno[2,3-d]pyrimidine derivatives with potential anticancer action, including 5a-l, 6, and 7a-b. Results from the NCI screening revealed that compounds 5f-i and 7a significantly inhibited the proliferation of MDA-MB-468 cells at mean GI% and GI50 levels. Compared to staurosporine, these compounds (5f-i and 7a) demonstrated better safety towards typical WI-38 cells. Compounds 5g and 7a demonstrated the highest inhibition (two-digit nanomolar) when compared to erlotinib when their potency was tested on EGFR kinase. Considering the outcomes above, 5g was examined for its ability to disrupt the cell cycle with trigger apoptosis in breast cancer MDA-MB-468 cell lines. The apoptosis markers Bax, Bcl-2, Caspase-8, and Caspase-9, were detected. In silico molecular docking and dynamic simulation were used to explain the biological activities of the most potent compound.
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DOI: 10.1016/j.bioorg.2023.106799
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