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Kinetic Analysis of the Stepwise Platination of Single‐ and Double‐Stranded GG Oligonucleotides with Cisplatin and cis ‐[PtCl(H 2 O)(NH 3 ) 2 ] +
Author(s) -
Sadler Peter J.,
Barnham Kevin J.,
BernersPrice Susan J.,
Frey Urban
Publication year - 1996
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.19960021016
Subject(s) - adduct , chemistry , stereochemistry , duplex (building) , cisplatin , oligonucleotide , nuclear magnetic resonance spectroscopy , dna , kinetics , hydrolysis , crystallography , medicinal chemistry , organic chemistry , biochemistry , medicine , physics , surgery , chemotherapy , quantum mechanics
We report the first direct comparison of the kinetics of platination of defined single‐ and double‐stranded DNA with the anticancer drug cisplatin. The courses of the reactions of the 14‐mer duplex d(A‐T‐A‐C‐A‐T‐G‐G‐T‐A‐C‐A‐T‐A)·d(T‐A‐T‐G‐T‐A‐C‐C‐A‐T‐G‐T‐A‐T) with [ 15 N]cisplatin and cis ‐[PtCl(H 2 O)‐( 15 NH 3 ) 2 ] + and of each of the single strands with [ 15 N]cisplatin have been studied at 298 K, pH 6, by [ 1 H, 15 N] NMR spectroscopy. As expected the reactions of cisplatin proceed via cis ‐[PtCl(H 2 O)(NH 3 ) 2 ] + , and lead to two monofunctional adducts on the duplex and two on the GG single strand. In both the GG single strand and the duplex, one of the two G's is platinated faster than the other (by a factor of ca. 4). Remarkably, ring closure on the duplex to form the GG chelate occurs about an order of magnitude faster for one monofunctional adduct than for the other. The latter monofunctional adduct has distinctive 1 H and 15 N NMR chemical shifts for Pt‐NH 3 , and is very long‐lived (persists for >5 d). The Pt‐Cl bond in this monofunctional adduct is protected from hydrolysis by the duplex. In contrast, the two monofunctional adducts on the GG single strand undergo ring closure at about the same rate. Equilibria between kinked and distorted forms of the GG platinated duplex, the platination of G's on the complementary strand, and the potential biological significance of long‐lived monofunctional adducts of platinum drugs with DNA are discussed.