Contrasting anticancer activity of half-sandwich iridium(III) complexes bearing functionally diverse 2-phenylpyridine ligands

We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(η5-Cp*)Ir(2-(R′-phenyl)-R-pyridine)Cl] bearing either an electron-donating (−OH, −CH2OH, −CH3) or electron-withdrawing (−F, −CHO, −NO2) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(η5-Cp*)Ir(2-(2′-fluorophenyl)pyridine)Cl] (1) and [(η5-Cp*)Ir(2-(4′-fluorophenyl)pyridine)Cl] (2) exhibit the expected “piano-stool” configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD+. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC50 values ranging from 1 to 89 μM, with the most potent complex, [(η5-Cp*)Ir(2-(2′-methylphenyl)pyridine)Cl] (13) (A2780 IC50 = 1.18 μM), being 10× more active than the parent, [(η5-Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(η5-CpxPh)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(η5-Cp*)Ir(2-(4′-fluorophenyl)pyridine)Cl] (2) and [(η5-Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] (4) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems

Influence of the binding of reduced NAMI-A to human serum albumin on the pharmacokinetics and biological activity

NAMI-A is a ruthenium-based drug endowed with the unique property of selectively targeting solid tumour metastases. Although two clinical studies had already been completed, limited information exists on the behavior of NAMI-A after injection into the bloodstream. PK data in humans informs us of a rather low free drug concentration, of a relatively high half-life time of elimination and of a linear relationship between the administered dose and the corresponding AUC for up to toxic doses. In the present study, we examined the chemical kinetics of albumin binding with or without the presence of reducing agents, and we evaluated how these chemical aspects might influence the in vivo PK and the in vitro ability of NAMI-A to inhibit cell migration, which is a bona fide, rapid and easy way to suggest anti-metastatic properties. The experimental data support the binding of NAMI-A to serum albumin. The reaction is facilitated when the drug is in its reduced form and, in agreement with already reported data, the adduct formed with albumin maintains the biological activity of the ruthenium drug. The formation of the adduct is favored by low ratios of NAMI-A\u2009:\u2009HSA and by the reduction of the drug with ascorbic acid. The difference in in vivo PK and the faster binding to albumin of the reduced NAMI-A seem to suggest that the drug is not rapidly reduced immediately upon injection, even at low doses. Most probably, cell and protein binding prevail over the reduction of the drug. This observation supports the thesis that the reduction of the drug before injection must be considered relevant for the pharmacological activity of NAMI-A against tumour metastases

Pt(II) complex containing the 1R,2R enantiomer of trans-1,2-diamino-4-cyclohexene ligand effectively and selectively inhibits the viability of aggressive pancreatic adenocarcinoma cells and alters their lipid metabolism

Here, we investigated the mechanism of antiproliferative action in cancer cells of new compounds structurally derived from oxaliplatin, namely a pair of enantiomers [Pt(OXA)(1R,2R-DACHEX)] (1) and [Pt(OXA)(1S,2S-DACHEX)] (2) (OXA = oxalate, DACHEX = trans-1,2-diamino-4-cyclohexene). While oxaliplatin is used almost exclusively to treat colorectal and other gastrointestinal cancers, new complex 1 shows instead high potency in malignant pancreatic adenocarcinoma PSN1 cells including superior selectivity for pancreatic cancer over noncancerous cells. Utilizing a multi-platform biochemical approach to study the unique features of the mechanism of action of this new platinum-based drug, we show that 1 has a much greater ability to penetrate pancreatic tumors than its S,S enantiomer 2 and oxaliplatin, and to be transported into cells as bound to plasma proteins. Additionally, the mechanism of action of 1 and, to a lesser extent, oxaliplatin in pancreatic cancer cells involves alterations of the lipogenesis pathway, namely inhibition of de novo lipid synthesis, acting by a new mechanism not yet considered for anticancer action of clinically used antitumor platinum drugs. These data highlight the functional diversity of platinum anticancer compounds and the potential benefits of finding new anticancer drugs applying a mechanism-based rationale

Novel Antitumor Cisplatin and Transplatin Derivatives Containing 1‑Methyl-7-Azaindole: Synthesis, Characterization, and Cellular Responses

The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compounds 1 and 2, respectively), on growth and viability of human carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The results show that substitution of 1-methyl-7-azaindole for ammine in cisplatin or transplatin results in an increase of the toxic efficiency, selectivity for tumor cells in cisplatin-resistant cancer cells, and activation of the trans geometry. The differences in the cytotoxic activities of 1 and 2 were suggested to be due to their different DNA binding mode, different capability to induce cell cycle perturbations, and fundamentally different role of transcription factor p53 in their mechanism of action. Interestingly, both isomers make it possible to detect their cellular uptake and distribution in living cells by confocal microscopy without their modification with an optically active ta