Unusual reactivity of cisplatin analogs that bear o-phenylenediamine ligands: insights for the design of more effective cytotoxic agents.
The stabilities of dichloro(o-phenylenediamine)platinum(II) (1) and several 4,5-disubstituted analogs [i.e., with: Cl (2), Br (3), Me (4), or MeO (5)] were investigated under various aqueous conditions. The Pt complexes 1-5- decomposed by reactions which were independent of the amount of chloride in the medium. The poor aqueous stabilities of 1-5 were attributed to two factors: 1) The compounds underwent facile oxidation reactions in aqueous solution at pH 7.4 and 37 degrees C, resulting in the formation of intensely colored Pt-species as well as H2O2. Compounds 2 and 3 oxidized considerably faster than 1, 4, and 5. Based on the redox behavior and UV-Vis spectra of the decomposition products, it is proposed that they are o-benzoquinonediimine Pt complexes. 2) Compound 4 underwent an unusually rapid substitution reaction with L-methionine, a component of the culture medium, whereby both of the chloro ligands of platinum were replaced by an N,S-chelated methionine. At an L-methionine concentration of 0.5 mM, the reaction ran to completion within 1 min. Thus, the weak growth inhibitory activities of 1-5 on human cancer cells in vitro was likely a result of their poor chemical stability in the culture medium. Based on a knowledge of the decomposition pathways, analogs were designed to be resistant to these types of reactions. Dichloro(o-aminomethylaniline)platinum(II) (6) and [bis-1,2(aminomethyl)benzene]-di-chloroplatinum(II) (7) were synthesized and their aqueous stabilities investigated. Both 6 and 7 were considerably more stable than 1-5 under aqueous conditions, as well as being more effective in inhibiting the growth of human cancer cells in vitro.
Köckerbauer
R
R
Lehrstuhl für Pharmazeutische Chemie II, Universität Regensburg, Germany.
Bednarski
P J
PJ
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D008715:Methionine / Q000737:chemistry; D010655:Phenylenediamines / Q000737:chemistry*; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays; D014867:Water
D000970:Antineoplastic Agents; D010655:Phenylenediamines; D014867:Water; D008715:Methionine; D006861:Hydrogen Peroxide; D002945:Cisplatin