Reversion of structure-activity relationships of antitumor platinum complexes by acetoxime but not hydroxylamine ligands
- Author(s)
- Stefanie Zorbas-Seifried, Michael Jakupec, Nikolay Kukushkin, Michael Größl, Christian Hartinger, Olga Semenova, Haralabos Zorbas, Vadim Yu Kukushkin, Bernhard Keppler
- Abstract
The presence of cis-configured exchangeable ligands has long been considered a prerequisite for antitumor activity of platinum complexes, but over the past few years, several examples violating this structure-activity relationship have been recognized. We report here on studies with the geometric isomers of [PtCl2(acetoxime)2], cis- [dichlorobis(acetoxime)platinum(II)] [1 (cis)] and trans-[dichlorobis(acetoxime) platinum(II)] [2 (trans)], as well as those of [PtCl2(hydroxylamine) 2], cis-[dichlorobis(hydroxylamine) platinum(II)] [3 (cis)] and trans-[dichlorobis(hydroxylamine) platinum(II)] [4 (trans)]. We found that 2 (trans) is 16 times more cytotoxic than 1 (cis) and as cytotoxic as cisplatin in cisplatin-sensitive ovarian carcinoma cells (CH1). Moreover, 2 (trans) is 15 times more cytotoxic than either cisplatin or 1 (cis) in intrinsically cisplatin-resistant colon carcinoma cells (SW480). Thus, compound 2 (trans) represents a novel type of active platinum(II) complexes of the trans geometry, whereas the hydroxylamine-containing complexes conform to the classic structure-activity relationships. The reactivity of the compounds toward dGMP and DNA and their capacity to alter the structure of double-stranded DNA and form interstrand crosslinks were studied by capillary electrophoresis and gel electrophoresis. The slow binding of 2 (trans) to dGMP (t1/2 = 50 h versus 8.9 h in the case of cisplatin), the low reactivity toward DNA, the comparatively small impact on DNA secondary structure, and the lack of detectable interstrand cross-linking suggest a mode of action fundamentally different from that of cisplatin. Implications of our findings for the minimal structural requirements (e.g., planarity around the nitrogen donor atom and/or ramified aliphatic moiety attached to the latter) of active trans-configured platinum complexes are discussed. Copyright © 2007 The American Society for Pharmacology and Experimental Therapeutics.
- Organisation(s)
- Department of Inorganic Chemistry, Department of Functional Materials and Catalysis
- External organisation(s)
- Max-Planck-Institut für Chemie (Otto-Hahn-Institut), Saint Petersburg State University, Ludwig-Maximilians-Universität München
- Journal
- Molecular Pharmacology
- Volume
- 71
- Pages
- 357-365
- No. of pages
- 9
- ISSN
- 0026-895X
- Publication date
- 2007
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/d24ae037-19bb-464d-99b0-a072e0aa10b9