Tuning of lipophilicity and cytotoxic potency by structural variation of anticancer platinum(IV) complexes

Reithofer, Michael R.; Bytzek, Anna K.; Valiahdi, Seied Mojtaba; Kowol, Christian R.; Groessl, Michael; Hartinger, Christian G.; Jakupec, Michael A.; Galanski, Markus; Keppler, Bernhard K.

doi:10.1016/j.jinorgbio.2010.09.006

Cited by 115 publications

(123 citation statements)

References 24 publications

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“…Furthermore, the novel dimeric platinum species 5a and 5b did not improve the cytotoxicity. log k w vs IC 50 In contrast to literature, where frequently a connection between cytotoxicity and lipophilicity was reported, 31,44 the here presented data show no evidence for a correlation between IC 50 and log k w in the cells investigated. The platinum(II) core seems to have a notable impact on the cytotoxicity, as all cisplatin derivatives show better or similar cytotoxicity than their N,N-dimethylethane-1,2-diamine counterparts featuring an increased log k w value.…”

Section: Cytotoxicity In Cancer Cell Linescontrasting

confidence: 99%

“…[24][25][26][27][28] Thus, the activity of these complexes depends on a range of bioinorganic and pharmacological attributes like the reduction potential, lipophilicity and solubility, binding behavior to biomolecules, and inertness with regard to ligand exchange reactions. [29][30][31] Several studies show that the type of axial ligands has an exceptionally high influence on the reduction potential and consequently on the cytotoxicity (chlorido ligands, high reduction potential and high cytotoxicity; hydroxido ligands, low reduction potential and low cytotoxicity). 32 As platinum(IV) drugs should ideally be reduced intracellularly, drug uptake into the cancer cell must occur before the reduction process takes place.…”

Section: Introductionmentioning

confidence: 99%

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Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

et al. 2012

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Eight novel mononuclear and two dinuclear platinum(IV) complexes were synthesized and characterized by elemental analysis, one-and two-dimensional NMR spectroscopy, mass spectrometry, and reversed-phase HPLC (log k w ) and in one case by X-ray diffraction. Cytotoxicity of the compounds was studied in three human cancer cell lines (CH1, SW480, and A549) by means of the MTT assay, featuring IC 50 values to the low micromolar range. Furthermore a selected set of compounds was investigated in additional cancer cell lines (P31 and P31/cis, A2780 and A2780/cis, SW1573, 2R120, and 2R160) with regard to their resistance patterns, offering a distinctly different scheme compared to cisplatin. To gain further insights into the mode of action, drug uptake, DNA synthesis inhibition, cell cycle effects, and induction of apoptosis were determined for two characteristic substances.

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Section: Cytotoxicity In Cancer Cell Linescontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

et al. 2012

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“…The log P values were determined according to the OECD guideline using a shake-flask method [25], as was previously done with platinum complexes [26][27][28]. Weighed amounts of platinum compounds were partitioned between an aqueous and a 1-octanol phase.…”

Section: Determination Of Log Pmentioning

confidence: 99%

Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues

et al. 2012

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The purpose of this study was to systematically investigate the relationships between reactivity, cellular accumulation, and cytotoxicity of a panel of oxaliplatin analogues with different leaving groups in human carcinoma cells. The reactivity of the complexes towards the nucleotides 2'-deoxyguanosine 5'-monophosphate and 2'-deoxyadenosine 5'-monophosphate was studied using capillary electrophoresis. Cellular accumulation and cytotoxicity were measured in an oxaliplatin-sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cell line pair (HCT-8/HCT-8ox). Platinum concentrations were determined by flameless atomic absorption spectrometry. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess cytotoxicity. Early cellular platinum accumulation was predominantly affected by lipophilicity. A relationship between reactivity and cellular accumulation was observed for three of four platinum complexes investigated, whereas the most lipophilic oxaliplatin analogue was an exception. Increased reactivity and reduced lipophilicity were associated with high cytotoxic activity. Resistance was influenced by lipophilicity but not by reactivity. The observed relationships may help in the design of analogues with high antitumoral activity in oxaliplatin-sensitive as well as oxaliplatin-resistant cells.

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“…Identified contributors to the reduction of Pt IV are small molecules such as glutathione (GSH) or ascorbic acid (AA), which are available in the blood stream as well as inside the cell, but also high molecular weight agents, such as metallothioneins, myoglobin and haemoglobin, are potential reductants. 4,5 The physicochemical parameters most decisive for where and whether the prodrug is reduced are the reduction potential 6,7 and the rate of reduction. [8][9][10][11][12] These parameters are strongly influenced by the ligand sphere of the central metal ion.…”

Section: Introductionmentioning

confidence: 99%

Influence of reducing agents on the cytotoxic activity of platinum(iv) complexes: induction of G2/M arrest, apoptosis and oxidative stress in A2780 and cisplatin resistant A2780cis cell lines

et al. 2015

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The concept of Pt(IV) prodrug design is one advanced strategy to increase the selectivity for cancer cells and to reduce systemic toxicity in comparison to established platinum-based chemotherapy. Pt(IV) complexes are thought to be activated by reduction via physiological reductants, such as ascorbic acid or glutathione. Nevertheless, only few investigations on the link between the reduction rate, which is influenced by the reductant, and the ligand sphere of the Pt(IV) metal centre have been performed so far. Herein, we investigated a set of Pt(IV) compounds with varying rates of reduction with respect to their cytotoxicity and drug accumulation in A2780 and A2780cis ovarian cancer cell lines, their influence on the cell cycle, efficiency of triggering apoptosis, and ability to interfere with plasmid DNA (pUC19). The effects caused by Pt(IV) compounds were compared without or with extracellularly added ascorbic acid and glutathione (or its precursor N-acetylcysteine) to gain understanding of the impact of increased levels of the reductant on the activity of such complexes. Our results demonstrate that reduction is required prior to plasmid interaction. Furthermore, the rate of reduction is crucial for the efficiency of this set of Pt(IV) compounds. The substances that are reduced least likely showed similar performances, whereas the fastest reducing substance was negatively affected by an increased extracellular level of reducing agents, with reduced cytotoxicity and lower efficiency in inducing apoptosis and G2/M arrest. These results confirm the connection between reduction and activity, and prove the strong impact of the reduction site on the activity of Pt(IV) complexes.

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Tuning of lipophilicity and cytotoxic potency by structural variation of anticancer platinum(IV) complexes

Cited by 115 publications

References 24 publications

Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues

Influence of reducing agents on the cytotoxic activity of platinum(iv) complexes: induction of G2/M arrest, apoptosis and oxidative stress in A2780 and cisplatin resistant A2780cis cell lines

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