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

Abstract

Benzyl amine was coupled to the dangling carboxylic acid groups of the platinum(II) complex [Pt(edda)Cl[subscript 2]], where edda = ethylenediamine-N,N′-diacetic acid, to give the diamide-tethered complex [Pt(L)Cl[subscript 2]] (1), where L = ethylenediamine-N,N′-bis(N-benzylacetamide). Complex 1 was oxidized with both PhICl[subscript 2] and Br[subscript 2]. Oxidation with PhICl[subscript 2] cleanly afforded the tetrachloride complex, [Pt(L)Cl[subscript 4]] (2), whereas oxidation with Br[subscript 2] gave rise to several mixed halide complexes of the general formula, [Pt(L)Cl[subscript x]Br[subscript 4-x]], where x = 1, 2, or 3. Complexes 1 and 2 were fully characterized by [superscript 1]H, [superscript 13]C, and [superscript 195]Pt 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[subscript x]Br[subscript y]] (3) are reported. Although refined as the tetrabromide complex [Pt(L)Br[subscript 4]], 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 IC[subscript 50] values close to 50 μM and are therefore substantially less toxic than cisplatin, for which the IC[subscript 50] is 1 μM.