Novel platinum(ii)-based anticancer complexes and molecular hosts as their drug delivery vehicles

Wheate, Nial J.; Taleb, Robin I.; Krause‐Heuer, Anwen M.; Cook, Rebekah L.; Wang, Shaoyu; Higgins, Vincent J.; Aldrich‐Wright, Janice R.

doi:10.1039/b704973k

Cited by 116 publications

(122 citation statements)

References 33 publications

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“…56MESS was synthesised as previously described [79]. [55] Cytotoxicity assay in cisplatin-resistant cell line L1210cisR and yeast…”

Section: Synthesis Of 56messmentioning

confidence: 99%

“…To date, [Pt(I L )(S,S-dach)] 2+ complexes have been more active than the R,R forms [18,42]. The complex [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) is more active than the other complexes so far tested [45, 55,79]. 56MESS is also shown to have more potent anticancer activity than cisplatin in a range of cisplatin-sensitive cancer cell lines (Table 1).…”

Section: Introductionmentioning

confidence: 99%

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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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“…56MESS was synthesised as previously described [79]. [55] Cytotoxicity assay in cisplatin-resistant cell line L1210cisR and yeast…”

Section: Synthesis Of 56messmentioning

confidence: 99%

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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“…Several derivatives of phenanthroline have been described, with varying degrees of activity against eukaryotic cells. [12,18,19] To further analyze the possible use of phenanthroline derivatives as anticancer drugs, as well as to assess their antimicrobial activities, two derivatives were synthesized: 1,10-phenanthroline-5,6-dione (phendione, L 1 ) [20] and dipyrido[3,2-a:2',3'-c]phenazine (dppz, L 2 ). These ligands were selected for their subtle differences in aromaticity and coordination properties over the parent ligand (phenanthroline, L 3 ).…”

Section: Chemical Synthesis and Structural Determinationmentioning

confidence: 99%

Phenanthroline Derivatives with Improved Selectivity as DNA‐Targeting Anticancer or Antimicrobial Drugs

et al. 2008

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Phenanthroline derivatives are of interest due to their potential activity against cancer, and viral, bacterial, and fungal infections. In a search for highly specific antitumor and antibacterial compounds, we report the activities of 1,10‐phenanthroline‐5,6‐dione (phendione or L1), dipyrido[3,2‐a:2′,3′‐c]phenazine (dppz or L2), and their corresponding platinum complexes ([PtL1Cl2] and [PtL2Cl2]), and provide the solid‐state 3D structure for [PtL1Cl2]. It is generally known that a toxic metal ion coordinated to an active organic moiety leads to a synergistic effect; however, we report herein that the platinum complexes [PtL1Cl2] and [PtL2Cl2] have weaker activities relative to those of the free ligands, especially against bacteria. Testing these agents against a variety of human cancer cell lines revealed that L1 and [PtL1Cl2] were at least as active as cisplatin against several of the cell lines (including a cisplatin‐resistant cell line). The absence of antibacterial activity of [PtL1Cl2] removes the detrimental effect of phenanthrolines toward intestinal flora, suggesting a highly promising new strategy for the development of anticancer drugs with reduced side effects.

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“…[1][2][3][4] It has demonstrated significant in vitro cytotoxicity in cisplatin sensitive and resistant human cancer cell lines. 5 56MESS is thought to induce cellular apoptosis by intercalating double-stranded DNA, thereby preventing DNA transcription and replication. 1 Drug transport, cellular uptake and intracellular glutathione degradation 6 are also thought to play a significant role in the structure-activity relationship of this family of platinum complexes.…”

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confidence: 99%

Diffusion-based studies on the self-stacking and nanorod formation of platinum(ii) intercalators

et al. 2009

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Pulsed gradient spin-echo nuclear magnetic resonance diffusion measurements have been used to show that platinum(II)-based intercalating agents self-stack in solution and form nanorods 0.45-3.9 nm in length (at 25 mM); their lengths are dependent on metal complex concentration, salt concentration and solution temperature.The anticancer agent 56MESS [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)] 2+ , Fig. 1a, is our lead candidate in a family of over 60 platinum(II)-based DNA intercalating complexes. [1][2][3][4] It has demonstrated significant in vitro cytotoxicity in cisplatin sensitive and resistant human cancer cell lines. 5 56MESS is thought to induce cellular apoptosis by intercalating double-stranded DNA, thereby preventing DNA transcription and replication. 1 Drug transport, cellular uptake and intracellular glutathione degradation 6 are also thought to play a significant role in the structure-activity relationship of this family of platinum complexes. 1 A number of new platinum(II)-based DNA intercalator complexes are also being developed that contain terpyridine intercalating groups (e.g. [(2,2 0 :6 0 ,2 00 -terpyridine)chloro-platinum(II)] + [Pt(terpy)Cl] + ; Fig. 1b). 7-9 A number of these compounds display activity similar to, or greater than, cisplatin in several cell lines. 10 It is widely accepted that compounds that contain fused aromatic rings are capable of forming dimers in solution through favourable p-p stacking. 11 Platinum(II) complexes containing planar aromatic ligands have been shown to stack and form dimers in aqueous solvents; however, these investigations have been limited to one-dimensional 1 H nuclear magnetic resonance (NMR) and electronic spectroscopy. [11][12][13][14] The formation of higher order aggregates (i.e. greater than two molecules) of these compounds has not been well demonstrated. The self-assembly of these complexes, particularly under physiological-like conditions, is of great importance, as aggregation may influence the ability of the complex to intercalate with DNA. In addition, the formation of large aggregates may influence the rate of drug transport/uptake. 15 56MESS and [Pt(terpy)Cl] + serve as excellent model compounds for initial investigations of such aggregation mechanisms. Thus, we have studied the self-aggregation of 56MESS and [Pt(terpy)Cl] + at varying metal complex/salt concentrations and solution temperatures using pulsed gradient spin-echo (PGSE) NMR diffusion measurements. 16 X-Ray crystal structures have shown that platinum(II)-based DNA intercalators can p-p stack in three different configurations; a head-to-head, 17 head-to-tail 18 or pinwheel configuration, where alternate intercalator molecules are rotated B901 compared to the molecule stacked above it. 2 In any configuration, the resultant macromolecule forms a cylinder or rod-like structure. We have employed the simple model of an ellipsoid (oblate or prolate, ESIw, Fig. S5) for the determination of macromolecule length. By substituting the observed diffusion coef...

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Novel platinum(ii)-based anticancer complexes and molecular hosts as their drug delivery vehicles

Cited by 116 publications

References 33 publications

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

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

Phenanthroline Derivatives with Improved Selectivity as DNA‐Targeting Anticancer or Antimicrobial Drugs

Diffusion-based studies on the self-stacking and nanorod formation of platinum(ii) intercalators

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