Cytotoxic trans‐Oriented Platinum Complexes only Form Adducts with Single‐Stranded Oligodeoxynucleotides

Abstract

The reactions of the anticancer complex trans-[PtCl(2)[(E)-HN==C(OMe)Me](2)] (trans-EE) with both single-stranded and double-stranded deoxyribonucleotides have been studied by HPLC and 2D [(1)H,(15)N] HMQC NMR spectroscopy and compared with those of cis-[PtCl(2)(NH(3))(2)] (cis-DDP). Reactions of trans-EE with the single-stranded oligonucleotides d(CCTCGCTCTC) and d(CCTGGTCC) proceed rapidly through solvolysis of the starting substrate and subsequent formation of G-N7/monochloro trans-EE adducts. The rate of reaction is comparable to that of formation of an adduct from trans-EE and the dinuclotide d(ApG). Quite unexpectedly, the double-helical duplexes, d(TATGGTACCATA)(2) and d(TATGGCCATA)(2), with no terminal G residues, are practically inert towards trans-EE, and only minor species (< 5 % as estimated from HPLC traces) appear during 24 h reaction time. However, the duplexes d[(CCTCGCTCTC). (GAGAGCGAGG)] and d(GATAGGCCTATC)(2), which contain both terminal and central G residues, undergo platination only at the terminal, solvent-exposed, G residues, thereby confirming that the interior of the duplex is not accessible to trans-EE due to steric hindrance. In contrast, cis-DDP was found to bind exclusively to the central GG pair in d(GATAGGCCTATC)(2).

Synthesis, Characterization, and In Vitro Antitumor Activity of New Amidineplatinum(II) Complexes Obtained by Addition of Ammonia to Coordinated Acetonitrile

“…Extensive mechanistic investigations performed on iminoether compounds indicate that these drugs form stable monofunctional adducts with DNA, which readily cross-link proteins. [20,21] The formation of DNA-protein crosslinks markedly inhibits not only the DNA synthesis by DNA polymerases, but also the removal of adducts from DNA by the nucleotide excision repair system. [22] Thus, the major role of the imine ligands would be to foster the formation of DNAprotein crosslinks mediated by platinum.…”

Internal versus Terminal Metalation of Double‐Helical Oligodeoxyribonucleotides

“…57 The results of this study show that cisplatin does not contain ligands that induce a significant steric hindrance for reactivity with DNA. On the contrary, we have recently shown that a promising antitumour trans ‐Pt II complex, containing bulky iminoether groups, only reacts with terminal guanines in double‐stranded DNA 58…”

Influence of dT20 and [d(AT)10]2 on Cisplatin Hydrolysis Studied by Two‐Dimensional [1H,15N] HMQC NMR Spectroscopy

“…We have also previously studied the rate of reaction between cisplatin and guanine-containing DNA oligonucleotides by two-dimensional (2D) [ 1 H, 15 N] HMQC NMR spectroscopy. [9] The work showed that the rapid reaction of 2 with guanine makes it impossible to determine the hydrolysis rate constants of cisplatin accurately. In the present work, we used less reactive DNA models (single-stranded dT 20 and duplex [d(AT) 10 ] 2 ) and, in contrast to the previous study, in which the pH was kept constant using a phosphate buffer, [8] we studied the cisplatin hydrolysis in unbuffered acidic solution.…”