Tumor-specific cytotoxicity of pyrazole-based chalcone derivatives in human oral squamous cell carcinoma cell lines

Background: Pyrazole-based chalcone hybrids are notable in medicinal chemistry for their potential biological activity. Their tumor-specific cytotoxicity and mechanisms remain unknown in OSCC cells. This is the first study of pyrazole–chalcone hybrids in OSCC cells. This study explores the tumor-selective cytotoxic effects and the underlying cell death mechanisms triggered by a series of ten newly synthesized pyrazole-based compounds (MS1–MS10) in OSCC cell lines.

Material and methods: The cytotoxic effects of the compounds were assessed using the MTT assay on four human OSCC cell lines and three types of normal human oral cells. Tumor-selectivity index (TS) and Potency-selectivity expression (PSE) were calculated. Active compounds were subjected to cell cycle analysis. For QSAR modeling, 3,096 descriptors comprising physicochemical, structural, and quantum chemical features were created using the most energetically advantageous conformations found from CORINA optimization.

Results: According to the results obtained, the compounds MS4 (PSE= 1443.6, TS= 71.2), MS7 (PSE= >15304.5, TS= >247.4), and MS8 (PSE= >7141.4, TS= >169.0) showed the highest TS and PSE values, comparable with doxorubicin and 5-FU. The cytotoxic compounds MS7 and MS8, as well as the cytostatic compound MS4, significantly (p<0.05) increased the cell population in the S and G2/M phases while decreasing the population in the G1 phase. Importantly, no significant accumulation was detected in the sub-G1 phase, which specifically indicates the absence of DNA fragmentation–associated apoptosis. QSAR analysis suggests the importance of 3D structure and lipophilicity in TS expression. ADMET analysis further revealed the drug-likeness properties of the active compounds, and the information obtained is expected to contribute significantly to the literature on the design and development of new compounds.

Conclusion: This study demonstrates the potent tumor-specific cytotoxic and cytostatic effects of pyrazole-based chalcone hybrids on OSCC cell lines, offering valuable insights for targeted anticancer drug development.