Molecular origin of the sequence-dependent kinetics of reactions between cisplatin derivatives and DNA

Experimental and theoretical studies related to the kinetics of interactions between cisplatin derivatives and DNA are critically reviewed. The reaction between DNA and cisplatin is a multistep reaction, consisting of aquation, electrostatic preassociation, nucleophilic substitution of one aqua ligand by a DNA guanine, and crosslink formation. If the reacting platinum complex is cis-PtCl(NH₃)₂(H₂O)]⁺, the monoadduct bears one chlorido ligand, and the crosslink formation is preceded by a second aquation step. The kinetics of all these steps, including that of the monoadduct aquation, is significantly modulated by the flanking bases. In the case of the cisplatin derivatives carboplatin and oxaliplatin, recent work has clearly shown that the opening of the dicarboxylate chelate ring is faster than cisplatin hydrolysis; however, the even much faster ring closure keeps the concentration of the ring-opened species very low. Correlation of data from reactions with nucleotides on the one hand and from those with DNA on the other hand indicates that in vitro, the reactions with DNA proceed with the intact dicarboxylates as the reacting species. Thus, for carboplatin and oxaliplatin, the species reacting with DNA are electroneutral, while for cisplatin, the reactive species are cationic. The fact that nevertheless the in vitro sequence-selectivities appear similar for all three complexes suggests that hydrogen bonding between platinum leaving groups and DNA residues is not a factor determining the sequence-selective binding to GG and AG sequences.This review focuses at the studies designed to quantify and explain the physical origin of the influence of DNA sequence on the reaction kinetics.