期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 139, 期 -, 页码 168-179出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.07.057
关键词
Spirooxindoles; Pyrazoline; Cytotoxicity; Anticancer agents; Colorectal cancer
资金
- Fundacao para a Ciencia e a Tecnologia, Portugal (FCT) [UID/DTP/04138/2013, SFRH/BPD/100961/2014]
- European Social Fund [IF/00732/2013]
- iMed.ULisboa through the Young Investigator's Project for Collaborative Cross-disciplinary Studies
- FCT, Programa Operacional Potencial Humano [IF/00732/2013]
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 mu M). 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
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