Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives
Paulina Strzyga‐Łach, Alicja Chrzanowska, Katarzyna Podsadni, Anna Bielenica
Abstract
Substituted thiourea derivatives possess confirmed cytotoxic activity towards cancer but also normal cells. To develop new selective antitumor agents, a series of 3-(trifluoromethyl)phenylthiourea analogs were synthesized, and their cytotoxicity was evaluated in vitro against the cell line panel. Compounds 1–5, 8, and 9 were highly cytotoxic against human colon (SW480, SW620) and prostate (PC3) cancer cells, and leukemia K-562 cell lines (IC50 ≤ 10 µM), with favorable selectivity over normal HaCaT cells. The derivatives exerted better growth inhibitory profiles towards selected tumor cells than the reference cisplatin. Compounds incorporating 3,4-dichloro- (2) and 4-CF3-phenyl (8) substituents displayed the highest activity (IC50 from 1.5 to 8.9 µM). The mechanisms of cytotoxic action of the most effective thioureas 1–3, 8, and 9 were studied, including the trypan blue exclusion test of cell viability, interleukin-6, and apoptosis assessments. Compounds reduced all cancerous cell numbers (especially SW480 and SW620) by 20–93%. Derivatives 2 and 8 diminished the viability of SW620 cells by 45–58%. Thioureas 1, 2, and 8 exerted strong pro-apoptotic activity. Compound 2 induced late apoptosis in both colon cancer cell lines (95–99%) and in K-562 cells (73%). All derivatives acted as inhibitors of IL-6 levels in both SW480 and SW620 cells, decreasing its secretion by 23–63%.