Oxidative reactivity and cytotoxic properties of a platinum(II) complex prepared by outer-sphere amide bond coupling

Benzyl amine was coupled to the dangling carboxylic acid groups of the platinum(II) complex [Pt(edda)Cl2], where edda = ethylenediamine-N,N′-diacetic acid, to give the diamide-tethered complex [Pt(L)Cl2] (1), where L = ethylenediamine-N,N′-bis(N-benzylacetamide). Complex 1 was oxidized with both PhICl2 and Br2. Oxidation with PhICl2 cleanly afforded the tetrachloride complex, [Pt(L)Cl4] (2), whereas oxidation with Br2 gave rise to several mixed halide complexes of the general formula, [Pt(L)ClxBr4-x], where x = 1, 2, or 3. Complexes 1 and 2 were fully characterized by 1H, 13C, and 195Pt NMR spectroscopy, as well as by ESI-MS. These compounds exist as a mixture of diastereomers that arise from the chirality of the two coordinated nitrogen atoms. Crystal structures of 1, 2, and [Pt(L)ClxBry] (3) are reported. Although refined as the tetrabromide complex [Pt(L)Br4], the crystal structure of 3 is a mixture of species with site-occupancy disorder of chloride and bromide ligands. DFT calculations indicate that the two sets of diastereomers of 1 and 2 are effectively thermoneutral, a conclusion that is also supported by the observation of both members of each pair by NMR spectroscopy. The cytotoxicity of 1 and 2 was measured by the MTT assay in HeLa cells and compared to that of cisplatin. Both exhibit IC50 values close to 50 μM and are therefore substantially less toxic than cisplatin, for which the IC50 is 1 μM.

Graphical abstractAn amide coupling reaction on the dangling carboxylic acids of the compound, [Pt(edda)Cl2], where edda is ethylenediamine-N,N′-diacetic acid, gave the new complex, [Pt(L)Cl2] (1) where L is ethylenediamine-N,N′-bis(N-benzylacetamide). The cytotoxic activity of 1 and its oxidative reactivity with PhICl2 and Br2 were investigated. The use of this general outer-sphere amide bond coupling reaction represents a new route to systematically modified platinum anticancer agents.Figure optionsDownload full-size imageDownload as PowerPoint slide