No abstract

Malignant pleural mesothelioma (MPM) cells are characterized by chemoresistance associated with glutathione (GSH) metabolism. Ethacrynic acid (EA) is able to inhibit the detoxifying enzyme glutathione-S-transferase (GST), which catalyzes the conjugation between GSH and Pt-based drugs. With the aim of obtaining active bifunctional drugs, a Pt(II) complex containing two EA moieties as leaving groups, namely cis-diamminobis(ethacrynato)platinum(II), was synthesized, characterized, and tested on four MPM cell lines. The resulting antiproliferative activity was compared with that elicited by the analogue Pt(IV) complex, cis,cis,trans-diamminodichloridobis(ethacrynato)platinum(IV) (ethacraplatin) and by the co-administration of free EA and cisplatin. The Pt(II) and Pt(IV) bifunctional complexes showed poorer performance than the reference drug cisplatin alone or in combination with EA. After treatment, cellular GST activity remained consistently unchanged, while the GSH level increased.

The kinetics of solvolysis in pure dimethyl sulfoxide (DMSO) and water/DMSO or water/dimethylformamide (DMF) mixtures of a series of variously N‐methylated ethylenediamine (en*) derivatives, cis‐[PtCl2(en*)], were studied by using an electrochemical biosensor consisting of DNA immobilized on the surface of screen‐printed electrodes, by conductivity measurements, and by multinuclear NMR spectroscopy and ESI‐MS techniques. The pattern of the kinetics was found to have significant differences between solvents, especially between the strongly coordinating DMSO and the weakly coordinating DMF co‐solvent, employed to increase the solubility of the complexes under study. In particular, cisplatin and cis‐[PtCl2(en*)] show rapid solvolysis in the former but significantly slower in the latter, which indicates that the affinity of the Pt core for the S‐donor atoms of DMSO overcomes the effect of its steric hindrance. In order to probe these reactions in more detail, density functional theory (DFT) calculations of activation barriers to solvolysis by both pure DMSO and H2O were performed.

The biological activity of four cisplatin-like Pt-phosphane complexes, namely, cis-[PtCl 2 (L) 2 ], L = PPh 3 , P(Ph) 2 (p-C 6 H 4 -COOH), P(Ph) 2 (-CH 2 CH 2 -COOH) and its succinimidyl ester derivative, has been tested on monolayer cultures of three tumour cell lines (namely, A2780 human ovarian carcinoma and its cisplatin-resistant form A2780Cp8, and human colon adenocarcinoma HCT116). These complexes can undergo intramolecular rearrangements by virtue of their functionalized phosphanes, thereby existing as fully opened (O) or fully closed (C) forms. Our results show that only the opened forms exhibit moderate activity, which, although inferior to the ac-[a]

We report on the results of electrochemical DNA biosensor assay of the interaction between double-stranded DNA (ds-DNA) and a series of six neutral, anionic or cationic Pt complexes of the general formula [PtCl n (NH 3 ) 4-n ](2-n) [n = 4, 1; n = 3, 2; n = 2, isomers cisplatin (3) and transplatin (4); n = 1, 5; n = 0, 6]. The ability of the electrophilic Pt II agents generated in solution to interact with DNA, and hence to form Pt-DNA adducts, was measured as a function of the decrease in the guanine oxidation signal recorded on a screen-printed