Synthesis, Characterization, and in Vitro Antitumor Activity of Ruthenium(II) Polypyridyl Complexes Tethering EGFR-Inhibiting 4-Anilinoquinazolines

Synthesis, Characterization, and in Vitro Antitumor Activity of Ruthenium(II) Polypyridyl Complexes Tethering EGFR-Inhibiting 4-Anilinoquinazolines

Ruthenium-based anticancer complexes are promising antitumor agents for their low system toxicity and versatile chemical structures. Epidermal growth factor receptor (EGFR) has been found to be overexpressed in a broad range of tumor cells and is regarded as a drug target in developing novel antitumor drugs. In this work, five ruthenium(II) polypyridyl complexes containing EGFR-inhibiting 4-anilinoquinazoline pharmacophores were synthesized and characterized. These complexes showed both high EGFR-inhibiting activity and strong DNA minor groove-binding activity. In vitro antiproliferation screening demonstrated that the prepared ruthenium complexes are highly cytotoxic against a series of cancer cell lines, in particular non-small-cell lung A549 and human epidermoid carcinoma A431. Fluorescence-activated cell sorting analysis and fluorescence microscopy revealed that the most active complex, K4, induced much more late-stage cell apoptosis and necrosis than gefitinib, the first EGFR-targeting antitumor drug in clinical use. These results indicate that the ruthenium(II) polypyridyl complexes bearing EGFR-inhibiting 4-anilinoquinazolines possess highly active dual-targeting anticancer activity and are promising in developing new anticancer agents.

基于钌的抗癌配合物因其低系统毒性和多样的化学结构，是很有前景的抗肿瘤药物。表皮生长因子受体（EGFR）已被发现在多种肿瘤细胞中过度表达，并被视为开发新型抗肿瘤药物的一个药物靶点。在这项工作中，合成并表征了五种含抑制EGFR的4 - 苯胺基喹唑啉药效团的钌（II）多吡啶配合物。这些配合物显示出高的抑制EGFR活性和强的DNA小沟结合活性。体外抗增殖筛选表明，所制备的钌配合物对一系列癌细胞系具有高度的细胞毒性，特别是对非小细胞肺癌A549和人表皮样癌A431。荧光激活细胞分选分析和荧光显微镜显示，活性最强的配合物K4比吉非替尼（临床上第一种靶向EGFR的抗肿瘤药物）诱导更多的晚期细胞凋亡和坏死。这些结果表明，含抑制EGFR的4 - 苯胺基喹唑啉的钌（II）多吡啶配合物具有高活性的双靶向抗癌活性，在开发新型抗癌药物方面很有前景。