Targeted suppression of oral squamous cell carcinoma by pyrimidine-tethered quinoxaline derivatives

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Oral cancer (OC) remains a leading cause of cancer mortality globally.
• Current therapies offer limited efficacy in extending patient survival.
• There is an urgent need for novel therapeutic strategies against OC.

Purpose of the Study:

• To design and synthesize novel quinoxaline-tethered imidazopyrimidine derivatives.
• To evaluate the in vitro anticancer activity of these compounds against OC cell lines.
• To investigate the mechanism of action of the most potent compounds.

Main Methods:

• Synthesis of twenty-five novel quinoxaline-tethered imidazopyrimidine derivatives.
• In vitro cytotoxicity assays using CAL-27 (OC) and normal oral epithelial (NOE) cell lines.
• Cell cycle analysis, apoptosis assays, in silico docking, and enzyme activity assays (PKM2 activation).

Main Results:

• Compound 12d exhibited potent antiproliferative activity against OC cells (IC50 = 0.79 μM) with minimal toxicity to NOE cells.
• 12d induced S-phase cell cycle arrest and promoted apoptosis in OC cells.
• In silico studies confirmed 12d binding to PKM2, and enzyme assays showed 12d as a potent PKM2 activator (AC50 = 0.6 nM).

Conclusions:

• The synthesized quinoxaline-tethered imidazopyrimidine derivatives show promise as novel anticancer agents for oral cancer.
• Compound 12d demonstrates significant potential as a therapeutic agent by targeting PKM2.
• This study provides a strong foundation for the development of new OC treatments.