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, although their tumor-specific cytotoxicity and mechanisms remain unknown in OSCC cells. This first study of pyrazole-chalcone hybrids in OSCC cells explores the tumor-selective cytotoxic effects and underlying cell death mechanisms triggered by a series of 10 newly synthesized pyrazole-based compounds (MS1MS10) 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. The tumor-selectivity index (TS) and potency-selectivity expression (PSE) were calculated, and active compounds were subjected to cell cycle analysis. For QSAR modeling, 3096 descriptors comprising physicochemical, structural, and quantum chemical features were created using the most energetically advantageous conformations found through CORINA optimization. Results: According to the obtained results, the compounds MS4 (PSE = 1443.6, TS = 71.2), MS7 (PSE > 15,304.5, TS > 247.4), and MS8 (PSE > 7141.4, TS > 169.0) showed the highest TS and PSE values, comparable to those of 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. Notably, no significant accumulation was detected in the sub-G1 phase, indicating the absence of DNA fragmentation-associated apoptosis. QSAR analysis suggests the importance of 3D structure and lipophilicity in TS expression, while ADMET analysis further revealed the drug-likeness properties of the active compounds. The obtained information 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.