title: Effect of thioethers on DNA platination by trans-platinum complexes.
abstract: Increasing evidence indicates that sulfur-containing molecules can play important roles in the activity of platinum anticancer drugs. Although nuclear DNA is retained to be the ultimate target, these platinum compounds can readily react with a variety of other substrates containing a soft donor atom, such as proteins, peptides, and low molecular weight biomolecules, before reaching DNA. In a recent study it was demonstrated that the DNA platination rate of a trans-geometry antitumor drug was dramatically enhanced by methionine binding, thus suggesting that the thioether could serve as a catalyst for DNA platination. In this work we performed detailed studies on the reactions of a widely investigated and very promising trans-platinum complex having two iminoethers and two chlorido ligands, trans-EE, with methionine (Met) and guanosine 5'-monophosphate (GMP). The results show that in the reaction of trans-EE with methionine the bisadduct is the dominant species in the early stage of the reaction. The reaction is also influenced by chloride concentration: at low NaCl the bis-methionine adduct is formed in preference, whereas the monoadduct is favored at high NaCl concentration. Not only the monomethionine complex, trans-PtCl(E-iminoether)(2)(AcMet), but also the bis-methionine adduct, trans-Pt(E-iminoether)(2)(AcMet)(2), which has already lost both leaving chlorides, can react with GMP to form the ternary platinum complex trans-Pt(E-iminoether)(2)(AcMet)(GMP). The latter reaction discloses the possibility of direct coordination to DNA of a platinum-protein adduct, in which the two carrier ligands remain intact; this is not the case of cis-oriented platinum complexes, like cisplatin, for which formation of a ternary complex is usually accompanied by loss of at least one carrier ligand. Interestingly, isomerization from S to N coordination of one methionine takes place in the bis-methionine complex at neutral pH, while the monoadduct appears to be stable. The shift from S to N coordination of one methionine in the trans-bis-methionine adduct can easily account for the obtainment of the cis isomer in the bis-chelated Pt(Met-S,N)(2) end product.
authors.affiliation: Department of Chemistry, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Li
authors.forename: Rongrong
authors.initials: R
authors.lastname: Huang
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Einar
authors.initials: E
authors.lastname: Sletten
authors.forename: Fabio
authors.initials: F
authors.lastname: Arnesano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Losacco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.forename: Yangzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D006157:Guanosine Monophosphate / Q000737:chemistry; D008024:Ligands; D008715:Methionine / Q000737:chemistry; D008968:Molecular Conformation; D008970:Molecular Weight; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D013440:Sulfides; D006157:Guanosine Monophosphate; D004247:DNA; D008715:Methionine