Spirotriazoline oxindoles: A novel chemical scaffold with in vitro anticancer properties.

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.

In vitro targeting of colon cancer cells using spiropyrazoline oxindoles.

We report on the synthesis and biological evaluation of a library of twenty-three spiropyrazoline oxindoles. The antiproliferative activity of the chemical library was evaluated in HCT-116 p53(+/+) human colon cancer cell line with eight derivatives displaying good activities (IC50<15 µM). To characterize the molecular mechanisms involved in compound antitumoral activity, two spiropyrazoline 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. Importantly, cytotoxic effects induced by spiropyrazolines oxindoles occurred in cancer cells without eliciting cell death in non-malignant CCD-18Co human colon fibroblasts. Additionally, we demonstrated that the combination of spiropyrazoline oxindole 2e with sub-toxic concentrations of the chemotherapeutic agent 5-fluorouracil (5-FU) exerted a synergistic inhibitory effect on HCT-116 colon cancer cell proliferation. Collectively, our results show the potential of spiropyrazoline oxindoles for development of novel anticancer agents.