In vitro targeting of colon cancer cells using spiropyrazoline oxindoles

Authors and Affiliations:

Rute C. Nunes, Carlos J. A. Ribeiro, Ângelo Monteiro, Cecília M. P. Rodrigues, Joana D. Amaral^*, Maria M. M. Santos^*

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa. Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal

Abstract:

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 anticanceragents.

Journal: European Journal of Medicinal Chemistry

Link: http://www.sciencedirect.com/science/article/pii/S0223523417305792