KINETIC-ANALYSIS OF THE STEPWISE PLATINATION OF SINGLE-STRANDED AND DOUBLE-STRANDED GG OLIGONUCLEOTIDES WITH CISPLATIN AND CIS-[PTCL(H2O)(NH3)(2)](+)

We report the first direct comparison of the kinetics of platination o f defined single- and double-stranded DNA with the anticancer drug cis platin. The courses of the reactions of the 14-mer duplex -A-T-G-G-T-A -C-A-TA)d(T-A-T-G-T-A-C-C-A-T-G-T-A-T) with [N-15]cisplatin and cis-[P tCl(H2O)-((NH3)-N-15)(2)](+) and of each of the single strands with [N -15]cisplatin have been studied at 298 K, pH 6, by [H-1,N-15] NMR spec troscopy. As expected the reactions of cisplatin proceed via cis-[Pt-C l(H2O)(NH3)(2)](+), and lead to two monofuntional adducts on the duple x and two on the GG single strand. In both the GG single strand and th e 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 monofunct ional adduct than for the other. The latter monofunctional adduct has distinctive H-1 and N-15 NMR chemical shifts for Pt-NH3, and is very l ong-lived (persists for > 5 d). The Pt-Cl bond in this monofunctional adduct is protected from hydrolysis by the duplex. In contrast, the tw o 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 complementa ry strand, and the potential biological significance of long-lived mon ofunctional adducts of platinum drugs with DNA are discussed.