Activation of trans geometry in bifunctional mononuclear platinum complexes by a piperidine ligand. Mechanistic studies on antitumor action

KAŠPÁRKOVÁ, Jana, Olga NOVAKOVÁ, María Victoria MARINI PALOMEQUE, Yousef NAJAJREH, Dan GIBSON, Jose-Manuel PEREZ and Viktor BRABEC. Activation of trans geometry in bifunctional mononuclear platinum complexes by a piperidine ligand. Mechanistic studies on antitumor action. Journal of Biological Chemistry. Bethesda, USA: Amer. Soc. Biochem. Mol. Biol., 2003, vol. 278, No 48, p. 47516-47525. ISSN 0021-9258.

Basic information

• Original name: Activation of trans geometry in bifunctional mononuclear platinum complexes by a piperidine ligand. Mechanistic studies on antitumor action
• Name in Czech: Aktivace trans geometrie bifunkcnich mononuklearnich platinovych komplexu piperidinovym ligandem.
• Authors: KAŠPÁRKOVÁ, Jana (203 Czech Republic), Olga NOVAKOVÁ (203 Czech Republic), María Victoria MARINI PALOMEQUE (858 Uruguay), Yousef NAJAJREH (275 Palestine, State of), Dan GIBSON (376 Israel), Jose-Manuel PEREZ (724 Spain) and Viktor BRABEC (203 Czech Republic, guarantor).
• Edition: Journal of Biological Chemistry, Bethesda, USA, Amer. Soc. Biochem. Mol. Biol. 2003, 0021-9258.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10610 Biophysics
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• Impact factor: Impact factor: 6.482
• RIV identification code: RIV/00216224:14310/03:00029122
• Organization unit: Faculty of Science
• Keywords in English: cisplatin; platinum complexes; DNA; antitumor
• Tags: antitumor, cisplatin, DNA, platinum complexes

Abstract

A paradigm for the structure-pharmacological activity relationship of bifunctional platinum antitumor drugs is that the trans isomer of antitumor cisplatin (transplatin) is clinically ineffective. To this end, however, several new complexes of the trans structure have been identified that exhibit cytotoxicity in tumor cells that is even better than that of the analogous cis isomers. We reported recently (Kasparkova, J., Marini, V., Najajreh, Y., Gibson, D., and Brabec, V. (2003) Biochemistry 42, 6321-6332) that the replacement of one ammine ligand by the heterocyclic ligand, such as piperidine, piperazine, or 4-picoline in the molecule of transplatin resulted in a radical enhancement of its cytotoxicity. We examined oligodeoxyribonucleotide duplexes bearing a site-specific cross-link of the transplatin analogue containing the piperidine ligand by biochemical methods. The results indicate that in contrast to transplatin, trans-(PtCl2(NH3)(piperidine)) forms stable 1,3-intrastrand cross-links in double-helical DNA that distort DNA and are not readily removed from DNA by nucleotide excision repair system. Hence, the intrastrand cross-links of trans-(PtCl2(NH3)(piperidine)) could persist for a sufficiently long time, potentiating its toxicity toward tumor cells. trans-(PtCl2(NH3)(piperidine)) also forms in DNA minor interstrand cross-links that are similar to those of transplatin so that these adducts appear less likely candidates for genotoxic lesion responsible for antitumor effects of trans-(PtCl2(NH3)(piperidine)). Hence, the role of structurally unique intrastrand cross-links in the anti-tumor effects of transplatin analogues in which one ammine group is replaced by a heterocyclic ligand may predominate.

Abstract (in Czech)

cz

Links

• GA305/02/1552, research and development project: Name: Oligonukleotidy modifikované komplexy platiny pro selektivní modulaci genové exprese; vztah k "protismyslné" strategii při vývoji nových farmak.