Structural studies on the interaction between a B-DNA duplex and Pt-based compounds

Metal-based therapy remains a highly utilized and effective option in the treatment of many types of cancer. However, due to the persistence of severe side effects and the increase of resistance events, new metal-based chemotherapeutics that could overcome these limitations are required. In this context, the investigation of the mode of action of these metal compounds and their interaction with nucleic acids or proteins is necessary and could benefit the design of new powerful antitumor drugs.

The most effective and extensively studied inorganic antitumor drug, which is able to interfere with DNA replication and transcription, is cisplatin ([cis-Pt(NH₃)₂Cl₂]). The first crystal structure of an adduct formed upon interaction of cisplatin with a B-DNA double helix (the dodecamer CGCGAATTCGCG) was solved by Dickerson in 1984. Cisplatin binds to the duplex via ligation to the N7 position of the major groove guanines that are characterized by a conformational mobility. Since the discovery of the antitumor activity of cisplatin, many new antitumor Pt-based compounds have been synthetized; detailed structural information on their interaction with DNA is still lacking.

With the aim to fill this gap, we studied the interaction of cisplatin, the iodinated derivative of cisplatin ([cis-Pt(NH₃)₂I₂]), carboplatin, oxaliplatin, and arsenoplatin-1 ([Pt(μ-NHC(CH₃)O)₂ClAs(OH)₂]), with the Dickerson sequence both in solution and at solid state. These studies could help to understand the different reactivity of the investigated compounds.