Capillary electrophoresis in anti‐cancer metallodrug research: Advances and future challenges

Hartinger, Christian G.; Timerbaev, Andrei R.; Keppler, Bernhard K.

doi:10.1002/elps.200305452

Cited by 57 publications

(40 citation statements)

References 82 publications

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“…CE has been used to determine chemical equilibria in proteinmetallodrug systems [49,50]. Compared with other separation-based assays such as highperformance liquid chromatography (HPLC), CE possesses distinctive advantages such as shorter analysis time, use of electrolyte compositions compatible with physiological incubation conditions, and no stationary phase involved in separation [51]. A similar approach as in the spectroscopic studies was followed with the HSA-to-site marker ratio kept constant and the KP1019 and KP1339 content was varied.…”

Section: Resultsmentioning

confidence: 99%

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

et al. 2012

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Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na + analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a non-covalent manner. In order to elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration−UV-vis spectrophotometry and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind into both sites with moderately to strong affinity (logK 1 ' = 5.3-5.8). No preference for either binding site was found and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event.

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Section: Resultsmentioning

confidence: 99%

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

et al. 2012

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“…5. Sequence analysis showed that both 3 and 4 preferentially attack at A, C, and G (and not T), as expected based on their different basicities [42].…”

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confidence: 83%

In vitro Ruthenation of Human Breast Cancer Suppressor Gene 1 (BRCA1) by the Antimetastasis Compound RAPTA‐C and Its Analogue CarboRAPTA‐C

Ratanaphan

Temboot

Dyson

2010

Chemistry & Biodiversity

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The interaction of two ruthenium-arene-1,3,5-triaza-7-phosphaadamantane compounds ([Ru(eta(6)-p-cymene)Cl(2)(pta)] and [Ru(eta(6)-p-cymene)(C(6)H(6)O(4))(pta)], termed RAPTA-C (3) and carboRAPTA-C (4), resp.) with the DNA sequence of the human breast-cancer suppressor gene 1 (BRCA1) has been studied using a range of techniques that probe conformation, cross-linking, base specificity, restriction analysis, and in vitro inhibition of DNA polymerization. The study demonstrates that substitution of the two labile chloride ligands in 3 by the more stable cyclobutane-1,1-dicarboxylate ligand onto the RAPTA framework reduces the rate of reaction with DNA in a similar manner to the analogous Pt-based drug pair cisplatin (1) and carboplatin (2), suggesting that hydrolysis may be a prerequisite to DNA binding with the Ru compounds. Moreover, the rate of DNA interaction for 3 is in a similar range to that of 2, despite the fact that these compounds have a different therapeutic profile. The similar rates of reaction contrasting with the different modes of activity suggests that the RAPTA compounds may be clinically useful against cancer cells that have developed resistance to Pt-based therapies, particularly involving excision-repair mechanisms.

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“…Capillary electrophoresis has often been applied to the analysis of platinum group complexes as well as their interaction with biomolecules in recent years (Hartinger et al, 2003;Timerbaev et al, 2006). DNA is considered the critical target for platinum complexes, and competitive studies including all four nucleobases confirmed guanine (and to a lesser extent adenine) as the preferred binding partner for the metal complexes-adduct formation takes place mainly via the N7 of the nucleobase (Martin, 1999).…”

Section: Downloaded Frommentioning

confidence: 99%

Reversion of Structure-Activity Relationships of Antitumor Platinum Complexes by Acetoxime but Not Hydroxylamine Ligands

Zorbas‐Seifried

Jakupec²,

Kukushkin³

et al. 2006

Mol Pharmacol

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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

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Capillary electrophoresis in anti‐cancer metallodrug research: Advances and future challenges

Cited by 57 publications

References 82 publications

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

In vitro Ruthenation of Human Breast Cancer Suppressor Gene 1 (BRCA1) by the Antimetastasis Compound RAPTA‐C and Its Analogue CarboRAPTA‐C

Reversion of Structure-Activity Relationships of Antitumor Platinum Complexes by Acetoxime but Not Hydroxylamine Ligands

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