Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Eur J Med Chem. 2017 Oct 20;139:168-179. doi: 10.1016/j.ejmech.2017.07.057. Epub 2017 Jul 24.
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 (IC<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.
我们报告了 23 个螺吡喃并吲哚啉的合成和生物学评估。用八种衍生物对 HCT-116 p53 人结肠癌细胞系进行了化学文库的抗增殖活性评估，其中 8 个衍生物显示出良好的活性（IC<15 μM）。为了表征化合物抗肿瘤活性所涉及的分子机制，选择了两种螺吡喃并吲哚啉进行进一步研究。这两种化合物均能诱导细胞凋亡和细胞周期停滞在 G0/G1 期，并上调 p53 的稳定水平，同时降低其主要抑制剂 MDM2。重要的是，螺吡喃并吲哚啉诱导的细胞毒性作用发生在癌细胞中，而不会在非恶性 CCD-18Co 人结肠成纤维细胞中引起细胞死亡。此外，我们证明了螺吡喃并吲哚啉 2e 与化疗药物 5-氟尿嘧啶（5-FU）的亚毒性浓度联合使用对 HCT-116 结肠癌细胞增殖具有协同抑制作用。总之，我们的研究结果表明螺吡喃并吲哚啉类化合物具有开发新型抗癌药物的潜力。
