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A Complete Kinetic Study of GG versus AG Platination Suggests That the Doubly Aquated Derivatives of Cisplatin Are the Actual DNA Binding Species
Author(s) -
Legendre Franck,
Bas Véronique,
Kozelka Jiří,
Chottard JeanClaude
Publication year - 2000
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 - 10.1002/1521-3765(20000602)6:11<2002::aid-chem2002>3.0.co;2-h
Subject(s) - chemistry , reaction rate constant , reactivity (psychology) , conjugate , chelation , cisplatin , stereochemistry , ligand (biochemistry) , medicinal chemistry , dna , aquation , base (topology) , oligonucleotide , hydrolysis , kinetics , inorganic chemistry , organic chemistry , medicine , mathematical analysis , biochemistry , physics , alternative medicine , mathematics , surgery , receptor , pathology , quantum mechanics , chemotherapy
The hairpin‐stabilized double‐stranded oligonucleotides d(TAT GG TATT 4 ATACCATA) ( I ) and d(TAT AG TATT 4 ATACTATA) ( II ) were allowed to react with the three aquated forms of the antitumor drug cisplatin ( cis ‐[PtCl 2 (NH 3 ) 2 ], 1 ) which are likely candidates for DNA binding, that is, cis ‐[PtCl(NH 3 ) 2 (H 2 O)] + ( 2 ), cis ‐[Pt(NH 3 ) 2 (H 2 O) 2 ] 2+ ( 3 ), and its conjugate base cis ‐[Pt(OH)(NH 3 ) 2 (H 2 O)] + ( 4 ). The reaction between I and [Pt(NH 3 ) 3 (H 2 O)] 2+ ( 5 ) was also studied for comparison. All reactions were monitored by HPLC. The platination reactions of I and II were carried out in NaClO 4 (0.1 M ) at 293 K and at a constant pH of 4.5±0.1 for 2, 3 , and 5 . The data relative to the platination by 4 were obtained from measurements in unbuffered NaClO 4 solutions (0.1 M ) at a starting pH close to neutrality, where 3 and 4 are present in equilibrium. In this case, a fit function describing the pH‐time curve allowed the determination of the actual concentrations of 3, 4 , and the dihydroxo complex. The platination rate constants characterizing the bimolecular reactions between either I or II and 2, 3 , and 4 were individually determined along with the rate constants for hydrolysis of the chloro‐monoadducts and for the chelation reactions of the aqua‐monoadducts. The reactivity of compounds 2 ‐ 5 , which have the general formula cis ‐[Pt(NH 3 ) 2 (H 2 O)(Y)] 2+/+ , decreases in the order 3 > 4 > 5 >> 2 , that is, Y=H 2 O>OH − >NH 3 >>Cl − , which is the order of decreasing hydrogen‐bond donating ability of Y. Deprotonation of 3 to 4 reduces the reactivity of the platinum complex only by a factor of ≈2, and both complexes discriminate between the different purines of I and II in the same manner. Whereas 3 and 4 react approximately three times faster with the GG sequence of I than with the AG sequence of II, 2 shows a similar reactivity towards both sequences. In view of the well‐established preferential binding of cisplatin to GG sequences of DNA in vivo and in vitro, this result suggests that the actual DNA platination species are derived from double hydrolysis of cisplatin.