title: Novel ruthenium complexes ligated with 4-anilinoquinazoline derivatives: synthesis, characterisation and preliminary evaluation of biological activity.
abstract: The ruthenium DMSO complexes cis-Ru(II)C12(DMSO)4 and [(DMSO)2H][trans-Ru(III)Cl4(DMSO)2] reacted with 4-(3'-chloro-4'-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline (L1), 4-(3'-chloro-4'-fluoroanilino)-6-(2-(1H-imidazol-1-yl)ethoxy)-7-methoxy quinazoline (L2), N-(benzo[d]imidazol-4-yl)-6,7-dimethoxyquinazolin-4-amine hydrochloride (L3), 5-(6,7-dimethoxyquinazolin-4-ylamino)quinolin-8-ol hydrochloride (L4), respectively, to afford [Ru(II)Cl2(DMSO)2(L1)] (1), [Ru(III)Cl3(DMSO)(L1)] (2), [Ru(III)Cl4(DMSO)(H-L2)] (3), [Ru(III)Cl4(DMSO)(H-L3)] (4), and [Ru(III)Cl3(DMSO)(H-L4)] (5), which were characterised by mass spectrometry, NMR, elementary analysis and single crystal X-ray diffraction (complex 1). Experimental screening (ELISA) showed that complexes 1, 2 and 3 are remarkably inhibitory towards epidermal growth factor receptor (EGFR) with IC50 values at submicromolar or nanomolar level. Docking studies indicated that complexation with ruthenium has little interference with the formation of the two essential H-bonds between the N3 of the quinazoline ring in L1 and L2 and O-H of Thr766 through a water molecule, and the N1 of the quinazoline ring and N-H of Met769 in EGFR. Moreover, complex 2 was shown to be more active against the EGF-stimulated proliferation of human breast cancer cell line MCF-7 than the better EGFR inhibitor 4-(3'-chloro-4'-fluoroanilino)-6,7-dimethoxyquinazoline, being more potential to induce early-stage apoptosis than gefitinib. These imply that apart from inhibiting EGFR, complex 2 may involve in regulating other biological events related to the proliferation of MCF-7, implicating a novel type of multi-targeting metal-based anticancer agents.
authors.affiliation: Beijing National Laboratory for Molecular Sciences, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Ji
authors.affiliation: Beijing National Laboratory for Molecular Sciences, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Beijing National Laboratory for Molecular Sciences, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, PR China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing National Laboratory for Molecular Sciences, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Lü
authors.affiliation: Beijing National Laboratory for Molecular Sciences, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Hao
authors.affiliation: Beijing National Laboratory for Molecular Sciences, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China. Electronic address: quoluo@iccas.ac.cn.
authors.forename: Qun
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Beijing National Laboratory for Molecular Sciences, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Xianchan
authors.initials: X
authors.lastname: Li
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Beijing National Laboratory for Molecular Sciences, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China. Electronic address: fuyi.wang@iccas.ac.cn.
authors.forename: Fuyi
authors.initials: F
authors.lastname: Wang
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011799:Quinazolines; D012428:Ruthenium; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Anticancer agents; EGFR inhibitors; MCF-7; Multi-targeting; Ruthenium complexes