Organoplatinum(II) Complexes Self-Assemble and Recognize AT-Rich Duplex DNA Sequences

Abstract

The specific recognition of AT-rich DNA sequences opens up the door to promising diagnostic and/or therapeutic strategies against gene-related diseases. Here, we demonstrate that amphiphilic Pt^II complexes of the type [Pt(dmba)(N∧N)]NO₃ (dmba = <i>N</i>,<i>N</i>-dimethylbenzylamine-κ<i>N,</i> κ<i>C</i>; N∧N = dpq (<b>3</b>), dppz (<b>4</b>), and dppn (<b>5</b>)) recognize AT-rich oligonucleotides over other types of DNA, RNA, and model proteins. The crystal structure of <b>4</b> shows the presence of significant π-stacking interactions and a distorted coordination sphere of the d⁸ Pt^II atom. Complex <b>5</b>, containing the largest π-conjugated ligand, forms supramolecular assemblies at high concentrations under aqueous environment. However, its aggregation can be promoted in the presence of DNA at concentrations as low as 10 μM in a process that "turns on" its excimer emission around 600 nm. Viscometry, gel electrophoresis, and theoretical calculations demonstrate that <b>5</b> binds to minor groove when self-assembled, while the monomers of <b>3</b> and <b>4</b> intercalate into the DNA. The complexes also inhibit cancer cell growth with low-micromolar IC₅₀ values in 2D tissue culture and suppress tumor growth in 3D tumor spheroids with a multicellular resistance (MCR) index comparable to that of cisplatin.