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 diamidetethered 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)Cl_xBr_4-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)Cl_xBr_y] (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.