Synthesis and characterization of quinazoline-based chiral thiourea derivatives and investigation of their cytotoxic and apoptotic effects on the MCF-7 cancer cell line

Breast cancer is one of the most common cancer types in women and represents a major health concern worldwide. The adverse effects and toxicity associated with existing chemotherapeutic agents necessitate the development of new and more effective anticancer compounds. In this study, the synthesis of novel quinazoline-based chiral thiourea compounds and the investigation of their biological activities were aimed based on the thiourea scaffold, which has been reported to exhibit various biological activities. Quinazolinone derivatives were synthesized from L-alanine, L-valine, and L-phenylalanine derivatives, followed by chlorination, reduction, and deprotection reactions to obtain chiral quinazoline amines. In the final step, the amines were reacted with aryl isothiocyanates to afford the target quinazoline-based chiral thiourea compounds in yields above 80%. The structures of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, and IR spectroscopy. Their antiproliferative activities were evaluated against MCF-7 human breast cancer and HUH-7 hepatocellular carcinoma cell lines using the MTT assay. In MCF-7 cells, particularly the 8a series compounds exhibited lower IC₅₀ values than carboplatin and docetaxel. The higher IC₅₀ values of the 8a series in HUH-7 cells compared with MCF-7 cells indicated differential sensitivity between the two cell models. However, HUH-7 cells should not be considered representative of normal liver cells. The apoptotic effect of the most active compound, 8a2, was further investigated using Annexin V-FITC/PI double staining and flow cytometry. A concentration-dependent increase in the proportion of apoptotic cells was observed after 24 h of treatment. These findings support further investigation of the antiproliferative effects of the 8a series, particularly in MCF-7 cells. Further studies involving selectivity assessment in different cancer and normal cell models, molecular mechanism investigations, and in vivo studies are required to evaluate these compounds as potential anticancer candidates.