Effect of the aniline fragment in Pt(II) and Pt(IV) complexes as anti-proliferative agents. Standard reduction potential as a more reliable parameter for Pt(IV) compounds than peak reduction potential

• Published in: Journal of inorganic biochemistry 2021-05, Vol.218, p.111403-111403, Article 111403
• Main Authors: Leal, Jorge, Santos, Lucia, Fernández-Aroca, Diego M., Cuevas, J. Vicente, Martínez, M. Angeles, Massaguer, Anna, Jalón, Felix A., Ruiz-Hidalgo, M. José, Sánchez-Prieto, Ricardo, Rodríguez, Ana M., Castañeda, Gregorio, Durá, Gema, Carrión, M. Carmen, Barrabés, Sílvia, Manzano, Blanca R.
• Format: Article
• Language: English
• Subjects: A549 Cells; Aniline; Aniline Compounds - chemistry; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Cancer; Cell Proliferation; HCT116 Cells; Heterocyclic ligands; Humans; MCF-7 Cells; Neoplasms - drug therapy; Neoplasms - pathology; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Platinum; Platinum - chemistry; Prodrugs - chemistry; Prodrugs - pharmacology; Pt(IV); Standard reduction potential
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2021.111403

The problems of resistance and side effects associated with cisplatin and other chemotherapeutic drugs have boosted research aimed at finding new compounds with improved properties. The use of platinum(IV) prodrugs is one alternative, although there is some controversy regarding the predictive ability of the peak reduction potentials. In the work described here a series of fourteen chloride Pt(II) and Pt(IV) compounds was synthesised and fully characterised. The compounds contain different bidentate arylazole heterocyclic ligands. Their cytotoxic properties against human lung carcinoma (A549), human breast carcinoma (MCF7) and human colon carcinoma (HCT116 and HT29) cell lines were studied. A clear relationship between the type of ligand and the anti-proliferative properties was found, with the best results obtained for the Pt(II) compound that contains an aniline fragment, (13), thus evidencing a positive effect of the NH2 group. Stability and aquation studies in DMSO, DMF and DMSO/water mixtures were carried out on the active complexes and an in-depth analysis of the two aquation processes, including DFT analysis, of 13 was undertaken. It was verified that DNA was the target and that cell death occurred by apoptosis in the case of 13. Furthermore, the cytotoxic derivatives did not exhibit haemolytic activity. The reduction of the Pt(IV) compounds whose Pt(II) congeners were active was studied by several techniques. It was concluded that the peak reduction potential was not useful to predict the ability for reduction. However, a correlation between the cytotoxic activity and the standard reduction potential was found. Synopsis for Graphical Abstract The cytotoxicity against different cancer cell lines of Pt(II) and Pt(IV) compounds containing heterocyclic ligands was studied with the best results obtained when a aniline fragment was present. DNA was the target. For the Pt(IV) compounds, the standard reduction potential was a more reliable parameter than the peak reduction potential. [Display omitted] •Standard reduction potential as predicting tool for Pt(IV) prodrugs.•A chloride Pt(II) complex with an aniline fragment very cytotoxic.•Study of two aquation processes by DFT analysis.