1360859-35-3Relevant academic research and scientific papers
Dual-targeting organometallic ruthenium(ii) anticancer complexes bearing EGFR-inhibiting 4-anilinoquinazoline ligands
Zhang, Yang,Zheng, Wei,Luo, Qun,Zhao, Yao,Zhang, Erlong,Liu, Suyan,Wang, Fuyi
, p. 13100 - 13111 (2015)
We have recently demonstrated that complexation with (η6-arene)RuII fragments confers 4-anilinoquinazoline pharmacophores a higher potential for inducing cellular apoptosis while preserving the highly inhibitory activity of 4-anilinoquinazolines against EGFR and the reactivity of the ruthenium centre to 9-ethylguanine (Chem. Commun., 2013, 49, 10224-10226). Reported herein are the synthesis, characterisation and evaluation of the biological activity of a new series of ruthenium(ii) complexes of the type [(η6-arene)Ru(N,N-L)Cl]PF6 (arene = p-cymene, benzene, 2-phenylethanol or indane, L = 4-anilinoquinazolines). These organometallic ruthenium complexes undergo fast hydrolysis in aqueous solution. Intriguingly, the ligation of (arene)RuII fragments with 4-anilinoquinazolines not only makes the target complexes excellent EGFR inhibitors, but also confers the complexes high affinity to bind to DNA minor grooves while maintaining their reactivity towards DNA bases, characterising them with dual-targeting properties. Molecular modelling studies reveal that the hydrolysis of these complexes is a favourable process which increases the affinity of the target complexes to bind to EGFR and DNA. In vitro biological activity assays show that most of this group of ruthenium complexes are selectively active inhibiting the EGF-stimulated growth of the HeLa cervical cancer cell line, and the most active complex [(η6-arene)Ru(N,N-L13)Cl]PF6 (4, IC50 = 1.36 μM, L13 = 4-(3′-chloro-4′-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline) is 29-fold more active than its analogue, [(η6-arene)Ru(N,N-ethylenediamine)Cl]PF6, and 21-fold more active than gefitinib, a well-known EGFR inhibitor in use clinically. These results highlight the strong promise to develop highly active ruthenium anticancer complexes by ligation of cytotoxic ruthenium pharmacophores with bioactive organic molecules.
Complexation with organometallic ruthenium pharmacophores enhances the ability of 4-anilinoquinazolines inducing apoptosis
Zheng, Wei,Luo, Qun,Lin, Yu,Zhao, Yao,Wang, Xiuli,Du, Zhifeng,Hao, Xiang,Yu, Yang,Lue, Shuang,Ji, Liyun,Li, Xianchan,Yang, Ling,Wang, Fuyi
, p. 10224 - 10226 (2013)
The complexation with organoruthenium fragments confers 4-anilinoquinazoline pharmacophores with higher potential for inducing cellular apoptosis while the highly inhibitory activity of 4-anilinoquinazolines against EGFR and the reactivity of the rutheniu
Novel ruthenium complexes ligated with 4-anilinoquinazoline derivatives: Synthesis, characterisation and preliminary evaluation of biological activity
Ji, Liyun,Zheng, Wei,Lin, Yu,Wang, Xiuli,Lü, Shuang,Hao, Xiang,Luo, Qun,Li, Xianchan,Yang, Ling,Wang, Fuyi
, p. 110 - 120 (2014/04/03)
The ruthenium DMSO complexes cis-RuIIC12(DMSO) 4 and [(DMSO)2H][trans-RuIIICl 4(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 [RuIICl 2(DMSO)2(L1)] (1), [RuIIICl3(DMSO) (L1)] (2), [RuIIICl4(DMSO)(H-L2)] (3), [Ru IIICl4(DMSO)(H-L3)] (4), and [RuIIICl 3(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.
Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors
Lue, Shuang,Zheng, Wei,Ji, Liyun,Luo, Qun,Hao, Xiang,Li, Xianchan,Wang, Fuyi
, p. 84 - 94 (2013/04/23)
We report here the design and synthesis of a series of 4-anilinoquinazoline derivatives, of which 7 compounds were crystallographically characterized, as epidermal growth factor receptor (EGFR) inhibitors by modifications on the aniline ring or at the 6-alkoxy site of the 6,7-dimethoxy-4-anilinoquinazoline pharmacophore. The relative inhibition efficiency on EGFR of all as-prepared compounds were measured and ordered, and the IC50 values of nine highly active compounds were determined by ELISA. Docking studies indicated that all 4-anilinoquinazoline derivatives could be inserted into the ATP-binding pocket of the EGFR via indirect docking, and that the modifications at the 3′-position of the anilino group and 6-alkoxy site of the quinazoline ring have little interference with the formation of the two essential H-bonds between the N3 of the quinazoline ring and Thr766 through a water molecule, and the N1 of the quinazoline ring and N-H of Met769. The displacing of the phenyl at 4-position with pyridinyl dramatically reduces the activity of the quinazoline pharmacophore, the resulting derivative (10) being the least active compound. The docking results also showed that the formation of new H-bonds between the N-H of the ethylenediamine group linked to the 6-alkoxy site and Asp776/Cys773 in the binding pocket of EGFR makes compounds 19 (IC50 = 12.1 ± 1.6 nM) and 20 (IC50 = 13.6 ± 0.8 nM) the most potent EGFR inhibitors in this class and worthy of further modification to obtain more potent anticancer compounds.
