Cytotoxicity of Alizarine versus Tetrabromocathecol Cyclometalated Pt(II) Theranostic Agents: A Combined Experimental and Computational Investigation

[Image: see text] Platinum compounds cytotoxicity is strictly related to their ability to be converted into active mono- and di-aquated species and consequently to the replacement of labile ligands by water molecules. This activation process makes the platinum center prone to nucleophilic substitution by DNA purines. In the present work, quantum mechanical density functional theory (DFT) computations and experimental investigations were carried out in order to shed light on the relationship between the internalization, aquation, and DNA binding of two isostructural anionic theranostic complexes previously reported by our group, NBu(4)[(PhPy)Pt(Aliz)], 1 (IC(50) 1.9 ± 1.6 μM), and NBu(4)[(PhPy)Pt(BrCat)], 2 (IC(50) 52.8 ± 3.9 μM). Cisplatin and a neutral compound [(NH(3))(2)Pt(Aliz)], 3, were also taken as reference compounds. The computed energy barriers and the endergonicity of the hydrolysis reactions showed that the aquation rates are comparable for 1 and 2, with a slightly higher reactivity of 1. The second hydrolysis process was proved to be the rate-determining step for both 1 and 2, unlike for compound 3. The nucleophilic attack by the N7 site of guanine to both mono- and di-aquated forms of the complexes was computationally investigated as well, allowing to rationalize the observed different cytotoxicity. Computational results were supported by photostability data and biological assays, demonstrating DNA as the main target for compound 1.