Synthesis, Characterisation and Biological Activity of Chiral Platinum(<scp>II</scp>) Complexes

Jaramillo, David; Buck, Damian P.; Collins, J. Grant; Fenton, Ronald R.; Stootman, F.; Wheate, Nial J.; Aldrich‐Wright, Janice R.

doi:10.1002/ejic.200500932

Cited by 52 publications

(51 citation statements)

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“…13 A prominent example is that no clear correlation has been found between the DNA binding affinity and the cytotoxicity of these complexes. 11,14,15 In this study, we have attempted to find such a correlation through both the synthesis of several platinum(II) anticancer complexes and the study of their DNA binding via fluorescent intercalator displacement assays (FIDs). The complexes synthesised here incorporated either dipyrido[3,2-f:2′,3′-h]quinoxaline (dpq) or 2,3-dimethyl-dpq (23Me 2 dpq) as an I L and one of the R,R or S,S isomers of either 1,2-diaminocyclohexane (SSdach or RR-dach) or 1,2-diaminocyclopentane (SS-dacp or RRdacp) as an A L (Fig.…”

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confidence: 99%

Synthesis and analysis of the anticancer activity of platinum(ii) complexes incorporating dipyridoquinoxaline variants

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Wormell

et al. 2014

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Eight platinum(II) complexes with anticancer potential have been synthesised and characterised. These complexes are of the type [, where I L is either dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or 2,3-dimethyl-dpq (23Me 2 dpq) and A L is one of the R,R or S,S isomers of either 1,2-diaminocyclohexane (SS-dach or RR-dach) or 1,2-diaminocyclopentane (SS-dacp or RR-dacp). The CT-DNA binding of these complexes and a series of other complexes were assessed using fluorescent intercalator displacement assays, resulting in unexpected trends in DNA binding affinity. The cytotoxicity of the eight synthesised compounds was determined in the L1210 cell line; the most cytotoxic of these were [Pt(dpq)(SS-dach)]Cl 2 and [Pt(dpq)(RR-dach)]Cl 2 , with IC 50 values of 0.19 and 0.80 μM, respectively. The X-ray crystal structure of the complex [Pt(dpq)(SS-dach)](ClO 4 ) 2 ·1.75H 2 O is also reported.

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Section: Introductionmentioning

confidence: 99%

Synthesis and analysis of the anticancer activity of platinum(ii) complexes incorporating dipyridoquinoxaline variants

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Wormell

et al. 2014

Dalton Trans.

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“…A class of square-planar platinum(II) metallointercalators has been developed of the type [Pt(I L )(A L )] 2+ , where I L can be 1,10-phenanthroline (phen) or substituted 1,10-phenanthroline and A L is achiral 1,2-diaminoethance (en) or chiral 1,2-diaminocyclohexane or (1S,3R)-1,3-diamino-1,2,2-trimethylcyclopentane [8,35,53]. They showed activity to a variety of cancer cell lines such as human colon cancer cell line (HCT8) and human lung cancer cell line (A-427) [45,55].…”

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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“…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.…”

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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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Synthesis, Characterisation and Biological Activity of Chiral Platinum(II) Complexes

Cited by 52 publications

References 29 publications

Synthesis and analysis of the anticancer activity of platinum(ii) complexes incorporating dipyridoquinoxaline variants

Synthesis and analysis of the anticancer activity of platinum(ii) complexes incorporating dipyridoquinoxaline variants

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

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

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