Possible incorporation of free N7-platinated guanines in DNA by DNA polymerases, relevance for the cisplatin mechanism of action

Cisplatin, cis-diamminedichloroplatinum(II), is one of the most widely used anticancer drugs. The main cellular target of cisplatin is DNA, where the platinum atom is able to form covalent bonds with the N7 of purines. It is commonly accepted that there is a direct attack of cisplatin to DNA. But it should be noted that, inside cells, free purine bases, which can react with cisplatin, are also available. Free bases have many functional roles, not least the constitution of building blocks for the synthesis of new DNA and RNA molecules. For this reason, under physiological conditions, the erroneous insertion of platinated bases in the synthesized nucleic acids could compete with direct DNA/RNA platination. Moreover, due to the lower sterical hindrance offered by single nucleobases with respect to nucleic acids, platination is expected to be even easier for free purines with respect to DNA and RNA. We have recently shown, for the first time, that platinated DNA can be formed in vitro by Taq DNA polymerase promoted incorporation of platinated purines. Cytotoxicity tests with [Pt(dien)(N7-G)], dien = diethylenetriamine, G = 5’-dGTP, 5’-dGDP, 5’-GMP, 5’-dGMP, GUO, dGUO, complexes on HeLa cancer cells support this hypothesis being the relative cytotoxicity of [Pt(dien)(N7-G)] derivatives clearly related to their bioavailability. In vivo platination of free purines before their incorporation in nucleic acids opens therefore new perspectives in platinum based antitumour drugs, for both action mechanism better understanding and new molecular design

A spectroscopic and electrochemical investigation of the oxidation pathway of glycyl-D,L-methionine and its N-acetyl derivative induced by gold(III)

The 1H nuclear magnetic resonance spectroscopy was applied to study the reaction of the dipeptide glycyl-D, L-methionine (H-Gly-D,L-Met-OH) and its N-acetylated derivative (Ac-Gly-D,L-Met-OH) with hydrogen tetrachloridoaurate(III) (H[AuCl 4]). The corresponding peptide and [AuCl 4] - were reacted in 1:1, 2:1, and 3:1 molar ratios, and all reactions were performed at pD 2.45 in 0.01 M DCl as solvent and at 25°C. It was found that the first step of these reactions is coordination of Au(III) to the thioether sulfur atom with formation of the gold(III)-peptide complex [AuCl 3(R-Gly-Met-OH-S)] (R=H or Ac). This intermediate gold(III) complex further reacts with an additional methionine residue to generate the R-Gly-Met-OH chlorosulfonium cation as the second intermediate product, which readily undergoes hydrolysis to give the corresponding sulfoxide. The oxidation of the methionine residue in the reaction between H-Gly-D,L-Met-OH and [AuCl 4]-was five times faster (k 2=0.363±0.074 M -1s -1) in comparison to the same process with N-acetylated derivative of this peptide (k 2=0.074±0.007 M -1s -1). The difference in the oxidation rates between these two peptides can be attributed to the free terminal amino group of H-Gly-D,L-Met-OH dipeptide. The mechanism of this redox process is discussed and, for its clarification, the reaction of the H-Gly-D,L-Met-OH dipeptide with [AuCl 4] - was additionally investigated by UV-Vis and cyclic voltammetry techniques. From these measurements, it was shown that the [AuCl 2] - complex under these experimental conditions has a strong tendency to disproportionate, forming [AuCl 4] - and metallic gold. This study contributes to a better understanding of the mechanism of the Au(III)-induced oxidation of methionine and methionine-containing peptides in relation to the severe toxicity of anti-arthritic and anticancer gold-based drugs. © The Author(s) 2011. This article is published with open access at Springerlink.com