Complexation with organometallic ruthenium pharmacophores enhances the ability of 4-anilinoquinazolines inducing apoptosis

Abstract

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 ruthenium centre to 9-ethylguanine are well preserved.

Discovery of a dual-targeting organometallic ruthenium complex with high activity inducing early stage apoptosis of cancer cells

“…38,43 Then the arene-ruthenium(II) dimer complex [(η 6 -p-cymene)RuCl 2 ] 2 was reacted with ligands L1 or L2 to produce complexes 1 or 2, respectively, and [(η 6 -pcymene)Ru(en)Cl][PF 6 ] was reacted with L3 or L4 to produce complexes 4 or 5, respectively. 30 Complexes 1 -5 have a derived quinazoline group which is the active site of gefitinib. Meanwhile, they have a halfsandwich ruthenium moiety, which is broadly regarded cytotoxic.…”

“…[6][7][8]27 For instance, the {(η 6 -arene)Ru} (arene = cyclopentadienyl, benzene, p-cymene, biphenyl, etc.) units can coordinate with ethylenediamine, imidazole, 2-(aminomethyl)pyridine, derived enzyme inhibitors to get a series of novel complexes with diverse biological activity and improved antitumour activity, 24,[28][29][30][31][32][33] indicating the possibility of organometallic ruthenium(II) arene complexes for the development of multi-functional antitumour drugs.…”

“…Among them, a Ru III complex and a Ru II complex, of which both contain the 4-anilinoquinazoline ligand 6-(2-(2-aminoethylamino)ethoxy)-4-(3'-chloro-4'-fluoroanilino)-7-methoxy-quinazoline (L0), exhibited excellent and selective antiproliferative activity towards the EGF (epidermal growth factor) stimulated growth of human MCF-7 breast cancer with better ability inducing apoptosis than the mono-functional EGFR-inhibiting gefitinib. 30,38 However, the complex [Ru III Cl 4 (DMSO)(L3)] (L3 = 6-(2-(2-(1H-imidazol-1-yl))ethoxy)-4-(3'-chloro-4'fluoroanilino)-7-methoxy-quinazoline, Scheme 1) exhibited little cytotoxicity towards MCF-7 cancer cell line (IC 50 > 100 µM), though it is more active against the enzyme activity of EGFR than the complex [Ru III Cl 3 (DMSO)(L0)]. 38 Since Ru II arene complexes usually possess higher cytotoxicity than Ru III complexes, 39 in order to improve the antitumour activity of Ru-L3 complexes, in this work, two complexes, [(η 6 -pcymene)Ru II (L3)Cl 2 ] (3) and [(η 6 -p-cymene)Ru II (en)L3] 2+ (4) were prepared.…”

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)

“…4-Anilinoquinazoline moieties, derivatives of the TKI gefitinib, were complexed with Ru(II) via an amine side chain, and shown to have enhanced ability for causing cellular apoptosis [ 170 ]. This is not surprising, as several Ru II and Ru III based complexes have shown promising anticancer and antimetastasis activities [ 171 ].…”

Metal‐Containing Pharmacophores in Molecularly Targeted Anticancer Therapies and Diagnostics

“…The aquated form of complex 8 (Figure ) binds to guanine bases in DNA with loss of aqua ligands. [39c] The arene ligands with extended ring systems, such as biphenyl moieties, were found to π‐stack with DNA bases or to intercalate partially into adjacent DNA base pairs, as observed in calf‐thymus DNA by UV/Vis spectroscopy and circular dichroism spectropolarimetry. Moreover, molecular docking studies also showed that the aquated Ru center was able to form two new hydrogen bonds in addition to the existing interactions between the organic 4‐anilinoquinazoline scaffold and the protein pocket, which would be predicted to enhance ligand binding.…”