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Digitale Medien

The new anticancer drug [(2R )-aminomethylpyrrolidine](1,1-cyclobutanedicarboxylato)platinum(II) and its toxic S enantiomer do interact differently with nucleic acids (1999)

Bloemink, Marieke J. ; Pérez, Janice M. J. ; Heetebrij, Robert J. ; [weitere]

Springer

JBIC 4 (1999), S. 554-567

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ISSN: 1432-1327

Schlagwort(e): Key words Cisplatin ; Carboplatin ; Antitumor actvity ; DNA binding ; Enantiomers

Quelle: Springer Online Journal Archives 1860-2000

Thema: Biologie , Chemie und Pharmazie

Notizen: Abstract The interaction of the two chiral isomers of the new anticancer agent [Pt(ampyr)(cbdca)] (ampyr=aminomethylpyrrolidine, cbdca=cyclobutanedicarboxylate) with 5′-GMP and with short G-containing oligonucleotides has been studied using 1H and 31P NMR, UV-vis spectroscopy and molecular modelling. Each isomer loses the cbdca ligand upon binding to the DNA fragments. Two geometrical isomers of the DNA adducts are formed owing to the presence of the unsymmetric ampyr ligand. These isomers prove to be GG-N7,N7 chelates for d(GpG), d(pGpG) and d(CpGpG). A slight preference for the formation of one geometrical isomer is found in the case of DNA fragments having a phosphate moiety and/or a C base at the 5′-site of the GG sequence. H-bonding interactions from the NH2 moiety towards the 5′-phosphate group and/or the O atom of the C base clearly favour the formation of one geometrical isomer. The presence of these H-bonds, together with the bulky pyrrolidine ring, has resulted in the unique observation (by 1H NMR) of NH protons of coordinated amines that do not rapidly exchange in a 99.95% D2O solution. Temperature-dependence studies show an extremely slow stack ⇄ destack conformational change for the CGG adducts of the S isomer, which could be related to these stable H-bonds of the amine protons towards the oligonucleotide. For the R isomer this stack ⇄ destack conformational change is faster, probably owing to more steric hindrance of the pyrrolidine ring as deduced from the NOESY data, and as also suggested by molecular modelling. The observation of extremely slow rotation around the Pt-N7 bond for [Pt(R-ampyr)(GMP-N7)2] provides further evidence for increased steric hindrance of the R isomer compared to the S isomer. The rate of binding of the drug to G bases proved to be second order for both isomers; in fact the (toxic) S isomer is about two times more reactive than the (non-toxic) R isomer, as seen from k 2 values of 0.17±0.01 M–1 s–1 for [Pt(S-ampyr)(cbdca)] and 0.09±0.01 M–1 s–1 for [Pt(R-ampyr)(cbdca)]. No solvent-assisted pathway is involved in these reactions, since the complexes prove to be stable in solution for weeks and therefore only a direct attack of the G base on the Pt must be involved. Because hardly any intermediate species can be detected during the reaction, coordination of the second G base must occur much faster than the binding of the first G base. Since direct attack of the nucleobases takes place, steric interactions become extremely important and therefore are likely to determine the reactivity, activity and even the toxicity of such Pt complexes.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/s007750050378

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Digitale Medien

Mechanistic studies of the oxidative coupling polymerization of phenols. VI.See Ref. 1 for previous paper in this series. Comparison of reactivities of DMP, PPO-dimer, and -trimer in the copper-catalyzed oxidative coupling polymerization (1992)

Viersen, F. J. ; Renkema, J. ; Challa, G. ; [weitere]

Bognor Regis [u.a.] : Wiley-Blackwell

Journal of Polymer Science Part A: Polymer Chemistry 30 (1992), S. 901-911

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ISSN: 0887-624X

Schlagwort(e): oxidative coupling polymerization ; poly(2,6-dimethyl-1,4-phenylene)oxide ; 2,6-dimethylphenol ; PPO-dimer ; PPO-trimer ; specificity ; reactivity ; flory principle of equal reactivity ; Chemistry ; Polymer and Materials Science

Quelle: Wiley InterScience Backfile Collection 1832-2000

Thema: Chemie und Pharmazie

Notizen: In the oxidative coupling polymerization, catalyzed by copper-amine complexes, the oxidation rates of 2,6-dimethylphenol (DMP) and its C—O-coupled dimer [4-(2′,6′-dimethylphenoxy)-2,6-dimethylphenol] and trimer [4-(-4′-(2″,6″-dimethylphenoxy)-2′,6′-dimethylphenoxy))-2,6-dimethylphenol] have been determined. The DMP concentration dependence shows a Michaelis-Menten-type behavior. On the other hand, the dimer and trimer showed a first-order rate-dependence in the respective phenol concentrations. This indicates that the slow reaction step, following an equilibrium complex formation between DMP and copper complex, is relatively fast for both the dimer and the trimer. Therefore, coordination of dimer or trimer to the copper complex appears to be rate-determining. Furthermore, the dimer and trimer gave overall reaction rates approximately eight times higher than found for DMP. Following the Flory principle of equal reactivity for functional groups of oligomers in polycondensations, all PPO oligomers can be assumed to have equally high oxidation rates as the dimer and trimer. The yield of undesired DPQ side product is strongly reduced when starting with the dimer (0.18%), or trimer (0.17%), compared to 3.3% for DMP. This is not unexpected, since DPQ can only be formed from two monomeric DMP residues. In fact, using a 1/10 molar mixture of dimer/DMP already results in a DPQ yield of only 1.7%. Furthermore, when starting from DMP, it has been observed that DPQ was predominantly formed during the first 30% conversion. Starting from dimer (or trimer) DPQ was formed at an almost constant very low rate during the whole course of the reaction. From these experiments it can be concluded that the most important polymerization reaction involves oxidation of copper-coordinated DMP anion to its corresponding cations, followed by coupling with a copper coordinated PPO chain.

Zusätzliches Material: 8 Ill.