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 generelated diseases. Here, we demonstrate that amphiphilic Pt-II complexes of the type [Pt(dmba)(NAN)]NO3 (dmba = N,N-dimethylbenzylamine-kappa N, kappa C; N Lambda N = dpq (3), dppz (4), and dppn (5)) recognize AT-rich oligonucleotides over other types of DNA, RNA, and model proteins. The crystal structure of 4 shows the presence of significant pi-stacking interactions and a distorted coordination sphere of the d(8) Pt-II atom. Complex 5, containing the largest Jrconjugated 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 mu M in a process that "turns on" its excimer emission around 600 nm. Viscometry, gel electrophoresis, and theoretical calculations demonstrate that 5 binds to minor groove when self-assembleff while the monomers of 3 and 4 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.