The design and synthesis of a library of twenty-six spirotriazoline
oxindoles and their in vitro evaluation as potential
anticancer agents is reported. The antiproliferative activity of the synthesized compounds was assessed against four different
cancer cell lines (HCT-116 p53(+/+), HCT-116 p53(-/-), MCF-7, and MDA-MB-231). Four spirotriazoline
oxindoles showed selectivity against the four
cancer cell lines tested over the non-
cancer derived HEK 293T cell line. To characterize the molecular mechanisms involved in compound antitumoral activity, two spirotriazoline
oxindoles were selected for further studies. Both compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase and upregulated p53 steady-state levels, while decreasing its main inhibitor MDM2, in HCT-116 cells. Importantly, cytotoxic effects induced by spirotriazoline
oxindoles occurred in
cancer cells without eliciting cell death in non-malignant CCD-18Co human colon fibroblasts. In addition, four spirotriazoline
oxindoles showed selectivity against the
triple-negative breast cancer cell line MDA-MB-231 with IC50 values of 3.5-6.7 μM. These results highlight the anticancer potential of spirotriazoline
oxindoles, especially when dealing with aggressive and challenging
triple-negative breast cancer.