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.
College of Chemistry and Materials Science, Key Laboratory of Functional Molecular Solids, the Ministry of Education, Anhui Laboratory of Molecular-Based Materials, Anhui Normal University , Wuhu 241000, People's Republic of China.
Jun
J
Du
College of Chemistry and Materials Science, Key Laboratory of Functional Molecular Solids, the Ministry of Education, Anhui Laboratory of Molecular-Based Materials, Anhui Normal University , Wuhu 241000, People's Republic of China.|Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Yan
Y
Kang
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Yao
Y
Zhao
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Wei
W
Zheng
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Yang
Y
Zhang
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Yu
Y
Lin
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Zhaoying
Z
Wang
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Yuanyuan
Y
Wang
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Qun
Q
Luo
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Kui
K
Wu
Beijing National Laboratory for Molecular Sciences; CAS Key Laboratory of Analytical Chemistry for Living Biosystems; Beijing Centre for Mass Spectrometry; Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, People's Republic of China.
Fuyi
F
Wang
D015082:2,2'-Dipyridyl / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005456:Fluorescent Dyes / Q000737:chemistry; D000077156:Gefitinib; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D056831:Coordination Complexes; D005456:Fluorescent Dyes; D008024:Ligands; D008565:Membrane Proteins; D010618:Phenanthrolines; D011799:Quinazolines; D015082:2,2'-Dipyridyl; D012428:Ruthenium; D004247:DNA; D066246:ErbB Receptors; C017807:bisbenzimide ethoxide trihydrochloride; D002945:Cisplatin; D000077156:Gefitinib