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Eur J Med Chem. 2017 Oct 20;139:168-179. doi: 10.1016/j.ejmech.2017.07.057. Epub 2017 Jul 24.

In vitro targeting of colon cancer cells using spiropyrazoline oxindoles.

Author information

1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
2
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address: jamaral@ff.ulisboa.pt.
3
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address: mariasantos@ff.ulisboa.pt/.

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 anticancer agents.

KEYWORDS:

Anticancer agents; Colorectal cancer; Cytotoxicity; Pyrazoline; Spirooxindoles

PMID:
28800455
DOI:
10.1016/j.ejmech.2017.07.057
[Indexed for MEDLINE]

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