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

• Published in: Inorganic chemistry Vol. 60; no. 4; pp. 2178 - 2187
• Main Authors: Zamora, Ana, Wachter, Erin, Vera, María, Heidary, David K, Rodríguez, Venancio, Ortega, Enrique, Fernández-Espín, Vanesa, Janiak, Christoph, Glazer, Edith C, Barone, Giampaolo, Ruiz, José
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.02.2021
• Subjects: A549 Cells; Coordination Complexes - chemistry; Crystallography, X-Ray; DNA - chemistry; Electrophoretic Mobility Shift Assay; Humans; Intercalating Agents - chemistry; Ligands; Molecular Structure; Organoplatinum Compounds - chemistry; Spectrum Analysis - methods; Stereoisomerism
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.0c02648

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 PtII complexes of the type [Pt­(dmba)­(N∧N)]­NO3 (dmba = N,N-dimethylbenzylamine-κN, κC; N∧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 π-stacking interactions and a distorted coordination sphere of the d8 PtII atom. Complex 5, 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 5 binds to minor groove when self-assembled, 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.