Multi-Nuclear Platinum Drugs: A New Paradigm in Chemotherapy

Wheate, Nial J.; Jg, Collins

doi:10.2174/1568011053765994

Cited by 93 publications

(73 citation statements)

References 97 publications

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“…Apoptotic and necrotic cells were differentiated according to the criteria described in Results. compounds [25][26][27][28] . Farrell et al synthesized a series of multinuclear platinum(II) complexes, which form DNA adducts that differ markedly in structure, sequence specificity and formation kinetics from those generated by cisplatin and its mononuclear analogs.…”

Section: Discussionmentioning

confidence: 99%

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

Czarnomysy

Bielawski²,

Muszyńska³

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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This study investigates the effect of three new platinum complexes: Pt2(2,4-dimethylpyridine)4(berenil)2 (Pt14), Pt2(3,4-dimethylpyridine)4(berenil)2 (Pt15) and Pt2(3,5-dimethylpyridine)4(berenil)2 (Pt16) on growth and viability of breast cancer cells and their putative mechanism(s) of cytotoxicity. Cytotoxicity was measured with MTT assay and inhibition of [3H]thymidine incorporation into DNA in both breast cancer cells. Results revealed that Pt14-Pt16 exhibit substantially greater cytotoxicity than cisplatin against MCF-7 and MDA-MB-231 breast cancer cells. In the case of human skin fibroblast cell, cytotoxicity assays demonstrated that these compounds are less toxic to normal cells than cisplatin. In addition, the effects of Pt14-Pt16 are investigated using the flow cytometry assessment of annexin V binding, analysis of mitochondrial potential, markers of apoptosis such as caspase-3, caspase-8, caspase-9, caspase-10 and defragmentation of DNA by TUNEL assay. These results indicate that Pt14-Pt16 induce apoptosis by the mitochondrial and external pathway.

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Section: Discussionmentioning

confidence: 99%

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

Czarnomysy

Bielawski²,

Muszyńska³

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Recently, platinum drugs with fundamentally different structures and binding modes to that of cisplatin have emerged [2,40]. Multi-nuclear platinum complexes, some of which are positively charged, capable of forming flexible and non-directional interstrand adducts with DNA have shown cytotoxic activity in tumour cells [40,52,78].…”

Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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“…5 Newer drugs, like the dinuclear complex CT-3610, are also just as Fig. 1 The chemical structures of cucurbit [7]uril (CB [7]) and the model dinuclear platinum anticancer complex: trans-[{PtCl (NH 3 susceptible to degradation, thus driving the need to develop delivery vehicles for this important class of drugs.…”

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confidence: 99%

A chemical preformulation study of a host–guest complex of cucurbit[7]uril and a multinuclear platinum agent for enhanced anticancer drug delivery

et al. 2009

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Single crystal and powder X-ray diffraction have been used to examine the host-guest complex of cucurbit [7]uril (CB [7]) and the model dinuclear platinum anticancer complex2+ (di-Pt, dpzm= 4,4¢-dipyrazolylmethane). The single crystal structure shows that the host-guest complex forms with the di-Pt dpzm ligand within the CB [7] cavity and with the platinum groups just beyond the macrocycle portals. Binding is stabilised through hydrophobic interactions and six hydrogen bonds between the platinum ammine ligands and the dpzm pyrazole amine to the CB [7] carbonyls. Each host-guest complex crystallises with two chloride counterions and 5.5 water molecules. The unit cell comprises four asymmetric units, each of which contains three crystallographically independent CB[7]-di-Pt moieties. X-Ray powder diffraction demonstrated structural consistency of the bulk crystals with a single polycrystalline phase that is identical with the single crystal structure. Finally, the effect of CB [7] encapsulation of the thermal stability of di-Pt was examined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). From the TGA experiments it was found that free CB [7] and the CB[7]-di-Pt complex lose 11 and 3.5% of their mass respectively, through the loss of water molecules, upon heating to 160• C. The DSC results showed that the free dpzm ligand melts between 186 and 199 • C, with a standard enthalpy of fusion of 27.92 kJ mol -1 . As a 2+ inorganic salt the metal complex does not melt but undergoes several decomposition events between 140 and 290• C. Encapsulation by CB [7] completely stabilises di-Pt with no decomposition of either the macrocycle or metal complex at temperatures up to 290 • C.

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Multi-Nuclear Platinum Drugs: A New Paradigm in Chemotherapy

Cited by 93 publications

References 97 publications

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

A chemical preformulation study of a host–guest complex of cucurbit[7]uril and a multinuclear platinum agent for enhanced anticancer drug delivery

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