一种体内活性的1,2,5-恶二唑铂（II）配合物：一种具有STAT3抑制特性的有前景的抗癌剂。
An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties.
作者信息
Porta Federica, Facchetti Giorgio, Ferri Nicola, Gelain Arianna, Meneghetti Fiorella, Villa Stefania, Barlocco Daniela, Masciocchi Daniela, Asai Akira, Miyoshi Nao, Marchianò Silvia, Kwon Byoung-Mog, Jin Yena, Gandin Valentina, Marzano Cristina, Rimoldi Isabella
机构信息
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via Marzolo 5, 35131, Padova, Italy.
出版信息
Eur J Med Chem. 2017 May 5;131:196-206. doi: 10.1016/j.ejmech.2017.03.017. Epub 2017 Mar 15.
New Pt(II) complexes (Pt-1-3) bearing 1,2,5-oxadiazole ligands (1-3) were synthesized, characterized and evaluated for their ability to disrupt STAT3 dimerization. Ligand 3·HCl showed cytotoxic effects on HCT-116 cells (IC = 95.2 μM) and a selective ability to interact with STAT3 (IC = 8.2 μM) versus STAT1 (IC > 30 μM). Its corresponding platinum complex Pt-3 exhibited an increased cytotoxicity (IC = 18.4 μM) and a stronger interaction with STAT3 (IC = 1.4 μM), leading to inhibition of its signaling pathway. Pt-3 was also evaluated in cell-based assays for its action on p53 expression and on STAT3 phosphorylation. In syngeneic murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice, Pt-3 showed a higher antitumor activity with fewer side effects than cisplatin.
合成了带有1,2,5-恶二唑配体（1-3）的新型铂（II）配合物（Pt-1-3），对其进行了表征，并评估了它们破坏信号转导和转录激活因子3（STAT3）二聚化的能力。配体3·HCl对人结肠癌细胞系HCT-116显示出细胞毒性作用（半数抑制浓度[IC] = 95.2 μM），并且与信号转导和转录激活因子3（IC = 8.2 μM）相比，对信号转导和转录激活因子1（IC > 30 μM）具有选择性相互作用能力。其相应的铂配合物Pt-3表现出增强的细胞毒性（IC = 18.4 μM）以及与信号转导和转录激活因子3更强的相互作用（IC = 1.4 μM），从而导致其信号通路受到抑制。还在基于细胞的试验中评估了Pt-3对p53表达和信号转导和转录激活因子3磷酸化的作用。在接种于C�7BL/6小鼠的同基因小鼠Lewis肺癌（LLC）模型中，Pt-3显示出比顺铂更高的抗肿瘤活性且副作用更少。
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