Received for publication September 14, 2006.
Revised October 18, 2006.
Accepted for publication October 18, 2006.

Reversion of structure-activity relationships of antitumor platinum complexes by acetoxime but not hydroxylamine ligands

Abstract

The presence of cis-configured exchangeable ligands has long been considered a prerequisite for antitumor activity of platinum complexes, but over the past years several examples violating this structure-activity relationship have been recognized. We report here on studies with the geometric isomers of [PtCl₂(acetoxime)₂], 1 (cis) and 2 (trans), as well as [PtCl₂(hydroxylamine)₂], 3 (cis) and 4 (trans). We found that 2 (trans) is 16 times more cytotoxic than 1 (cis) and equally cytotoxic as cisplatin in cisplatin-sensitive ovarian carcinoma cells (CH1). Moreover, 2 (trans) is 15 times more cytotoxic than both cisplatin and 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 as well as their capacity of altering the structure of dsDNA and forming interstrand cross-links were studied by capillary electrophoresis and gel electrophoresis. The slow binding of 2 (trans) to dGMP (_1/2 = 50 h vs. 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.

Key words: Structure-activity relationships and modeling, DNA damage and repair