(Aminoethanol)dichloroplatinum(II) complexes: influence of the hydroxyethyl moiety on 5'-GMP and DNA binding, intramolecular stability, the partition coefficient and anticancer activity.
The influence of tethered hydroxyl groups on the binding behavior of the three (aminoethanol)dichloroplatinum complexes, dichloro(N,N'-bis(2-hydroxyethyl)ethylenediamine)-platinum(II) (1), dichloro(N-(2-hydroxyethyl)ethylenediamine)platinum(II) (2) and cis-dichlorobis(2-hydroxyethylamine)platinum(II) (3) towards 5'-GMP and DNA was investigated by 1H NMR and r(b) measurements, respectively. At pH 7.2, the sequence of reactivity with 5'-GMP is 1>2>>3. Complex 3 reacts very slowly with 5'-GMP and DNA and the amount and lifetime of the intermediate 5'-GMP monoadduct are much larger than for 1 and 2. At pH 5.5, the reaction of 3 with 5'-GMP is markedly accelerated and very small amounts of monoadduct are observed, indicating a pH-dependent ability of the pendant hydroxyl group to interact with the platinum moiety. In addition, the effect of the hydroxyethyl functionality on octanol/water partitioning and in vitro anticancer activity was studied. No correlation between lipophilicity and anticancer activity was detected. Furthermore, the lipophilicity and anticancer activity could not be directly correlated to 5'-GMP or DNA binding activity.
Robillard
Marc S
MS
Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Galanski
Mathea S
MS
Zimmermann
Wolfgang
W
Keppler
Bernard K
BK
Reedijk
Jan
J
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008819:Mice, Nude; D019906:Nuclear Magnetic Resonance, Biomolecular; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D006157:Guanosine Monophosphate; D004247:DNA