Novel half-sandwich iridium(iii) imino-pyridyl complexes showing remarkable in vitro anticancer activity

Abstract

Seven novel half-sandwich Ir cyclopentadienyl complexes, [(η-Cp)Ir(N^N)Cl]PF, have been prepared and characterized, where Cp is Cp* or the biphenyl derivative Cp (CMeCHCH), and the N^N-chelating ligands are imino-pyridyl Schiff-bases. The X-ray crystal structures of complexes 2A, 2B, and 3A have been determined. Excitingly, most of the complexes show potent antiproliferative activity towards A549 and HeLa cancer cells, except for Cp* complex 1A towards HeLa cells. Cp complex 2B displayed the highest potency, about 19 and 6 times more active than the clinically used drug cisplatin toward A549 and HeLa cells, respectively. These complexes undergo hydrolysis, and the kinetics data have been calculated. DNA binding has been studied by interaction with nucleobases 9-ethylguanine and 9-methyladenine, cleavage of plasmid DNA, and interaction with ctDNA. Interaction with DNA does not appear to be the major mechanism of action. Protein binding (bovine serum albumin, BSA) has been established by UV-Vis, fluorescence and synchronous spectroscopic studies. The stability of complex 2B in the presence of GSH was evaluated. The complexes catalytically convert coenzyme NADH to NADvia hydride transfer. Cp complexes 2B and 4B induce cell apoptosis and arrest cell cycles at the S and G/M phases towards A549 cancer cells and increase the reactive oxygen species dramatically, which appear to contribute to the remarkable anticancer activity.

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

“…The antiproliferative activity of 3C was evaluated against the normal cell line BEAS‐2B (human bronchial epithelial cells) with IC 50 value of 3.8 μM, suggesting no selectivity between cancer and normal cells (Table ). We have reported half‐sandwich iridium complexes containing N^N‐chelating iminopyridyl ligands that displayed highly potent antiproliferative activity against cancer cells, but poor cytotoxic selectivity between cancer and normal cells . Substitution of cyclopentadienyl iridium moiety with ruthenium benzene led to a decrease of potency but better cytotoxic selectivity, suggested that the metals play a vital role in anticancer activity.…”

Experimental and theoretical investigation of cyclometalated phenylpyridine iridium(iii) complex based on flavonol and ibuprofen ligands as potent antioxidant

“…[10][11][12][13][14] In particular, there have been several attempts to use Ir-based carbene compounds or complexes as antitumor agents; a series of half-sandwich Ir(III) complexes were synthesized or modeled and reported as potential anticancer drugs. [15][16][17][18][19][20] Indeed, one can expect for the new Ir(III) complexes, as well as for other metallodrugs, to (i) get stronger and more selective effects against tumors, (ii) extend the spectrum of cancer treatment and (iii) overcome the limits of Pt-based drugs such as the platin resistance and other severe side-effects.…”

Triphenylamine‐Appended Half‐Sandwich Iridium(III) Complexes and Their Biological Applications

“…The interaction of base pairs of DNA with complexes usually involves intercalation, interaction, non-intercalative electrostatic interactions as wella sd amage of the DNA double helix. [42][43][44][45] The change in the absorption wavelength of the as-synthesized complexes as the amount of CT-DNA (DNA sodium from calf thymus) increased was determined by means of UV/Vis titration, and the bindingc onstants( K b )o ft he complexes were also calculated. The role of metal iridium in our complexes is probablyt op rovideacoordination center.…”