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 few years, several examples violating this structure-activity relationship have been recognized. We report here on studies with the geometric isomers of [PtCl 2 (acetoxime) . 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 ( 1/2 ϭ 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.The resounding success of cisplatin in tumor therapy, in particular that for testicular cancer, has set off tremendous efforts to produce other platinum drugs with comparable therapeutic value but devoid of its shortcomings (Wong and Giandomenico, 1999;Jakupec et al., 2003). Despite the achievements of carboplatin and oxaliplatin, the chances of effecting considerable advances with complexes following the classic structure-activity relationships seem to become gradually exhausted, forcing investigators to focus their efforts on nonclassic structures that might open up new avenues.The classic structure-activity relationships, as inferred from cisplatin/transplatin and related complexes, implied that the presence of two monodentate or one bidentate exchangeable ligand(s) coordinated in the cis geometry is an

In Vitro Anticancer Activity and Biologically Relevant Metabolization of Organometallic Ruthenium Complexes with Carbohydrate‐Based Ligands

“…[51,[55][56][57][58][59] Interaction of 1 with the model compound 9-ethylguanine (9EtG) was investigated under different conditions. Incubation of 1 with 9EtG at molar ratios of 1:1 and 1:2 resulted in formation of the respective 9EtG adduct by exchange of a chlorido ligand (two diastereomers at approximately 139 and 141 ppm in the Mass spectrometric studies of a mixture of 1 and 9EtG (1:1) after 24 h of reaction revealed, in addition to a peak assignable to unchanged 9EtG at m/z 180.…”

Capillary electrophoresis hyphenated to inductively coupled plasma‐mass spectrometry: A novel approach for the analysis of anticancer metallodrugs in human serum and plasma

“…It has been applied to investigate the stability of novel compounds but also the interactions of drugs with biomolecules, such as human serum proteins [8][9][10][11][12][13][14][15] and nucleotides [16][17][18][19][20][21], elucidating possible metabolic and reaction pathways of the drug candidates [6,7,16], notably always working under simulated physiological conditions with regard to pH, temperature, aqueous solutions, and/or buffer composition.…”

CE in anticancer metallodrug research – an update

“…Recently, the binding of 5 0 -dGMP toward a series of cis-and trans-Pt(II) amine (cisplatin and transplatin, acetoxime, and hydroxylamine compounds; for structural formulae see Fig. 1) was studied by CZE and the binding was compared to that of plasmid DNA and a dsDNA fragment by gel electrophoresis [56]. The formation of 5 0 -dGMP adducts of the platinum complexes could be followed by CZE with UV/Vis detection, which is quite indicative for the formation of such species.…”