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Cytotoxic trans ‐Oriented Platinum Complexes only Form Adducts with Single‐Stranded Oligodeoxynucleotides
Author(s) -
Vinje Jo,
Intini Francesco P.,
Natile Giovanni,
Sletten Einar
Publication year - 2004
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200400118
Subject(s) - adduct , chemistry , stereochemistry , steric effects , oligonucleotide , deoxyribonucleotides , solvolysis , nuclear magnetic resonance spectroscopy , dna , nucleotide , biochemistry , organic chemistry , hydrolysis , gene
The reactions of the anticancer complex trans ‐[PtCl 2 {( E )‐HNC(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 .