Anwen M. Krause-Heuer

Advances in Platinum Chemotherapeutics

The approved platinum(II)-based anticancer agents cisplatin, carboplatin and oxaliplatin are widely utilised in the clinic, although with numerous disadvantages. With the aim of circumventing unwanted side-effects, a great deal of research is being conducted in the areas of cancer-specific targeting, drug administration and drug delivery. The targeting of platinum complexes to cancerous tissues can be achieved by the attachment of small molecules with biological significance. In addition, the administration of platinum complexes in the form of platinum(IV) allows for intracellular reduction to release the active form of the drug, cisplatin. Drug delivery includes such technologies as liposomes, dendrimers, polymers and nanotubes, with all showing promise for the delivery of platinum compounds. In this paper we highlight some of the recent advances in the field of platinum chemotherapeutics, with a focus on the technologies that attempt to utilise the cytotoxic nature of cisplatin, whilst improving drug targeting to reduce side-effects.

Transition Metal Based Anticancer Drugs

With an ageing baby-boomer population in the Western World, cancer is becoming a significant cause of death. The prevalence of cancer and all associated costs, both in human and financial terms, drives the search for new therapeutic drugs and treatments. Platinum anticancer agents, such as cisplatin have been highly successful but there are several disadvantages associated with their use. What is need are new compounds with different mechanisms of action and resistance profiles. What needs to be recognised is that there are many other metal in the periodic table with therapeutic potential. Here we have highlighted metal complexes with activity and have illustrate the different approaches to the design of anticancer complexes.

Studies of the mechanism of action of platinum(II) complexes with potent cytotoxicity in human cancer cells.

We have examined the biological activity of 12 platinum(II)-based DNA intercalators of the type [Pt(I(L))(A(L))](2+), where I(L) is an intercalating ligand (1,10-phenanthroline or a methylated derivative) and A(L) is an ancillary ligand (diaminocyclohexane, diphenylethylenediamine or 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine). The chiral compounds (1-9) and the racemic compounds (10-12) were tested against a panel of human cancer cell lines, with a number of complexes displaying activity significantly greater than that of cisplatin (up to 100-fold increase in activity in the A-427 cell line). The activity of the complexes containing diphenylethylenediamine (8 and 9) and 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine (10-12) was significantly lower compared to the complexes containing diaminocyclohexane (1-7). Further in vitro testing, such as DNA unwinding, competition assays, and DNase 1 footprinting, was conducted on the most active compound (5) and its enantiomer (6) to provide information about the mechanism of action. These complexes display activity in cisplatin resistant cell lines, have higher cellular uptake than cisplatin, and do not activate caspase-3 as cisplatin does, indicating that these complexes exhibit a different mechanism of action.

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

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.

Copper(ii) and palladium(ii) complexes with cytotoxic and antibacterial activity

The synthesis of eight square pyramidal copper complexes with general structure [Cu(IL)(AL)H2O]2+, where IL represents various methylated 1,10-phenanthrolines, and AL represents either 1S,2S- or 1R,2R-diaminocyclohexane, is reported, with the complexes synthesised as both the perchlorate and chloride salts. The crystal structures of [Cu(1,10-phenanthroline)(1S,2S-diaminocyclohexane](ClO4)2·H2O and [Cu(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane](ClO4)2·1.5H2O are reported. Four square planar palladium complexes with general structure [Pd(IL)(AL)]Cl2 have also been synthesised. These complexes were synthesised in order to investigate the structure–activity relationship against both cancer cell lines and bacterial cultures. The copper complexes display anticancer activity similar to cisplatin and 1,10-phenanthroline (phen) in the L1210 murine leukaemia cell line. Methylation of the phen increased the copper complex cytotoxicity by approximately four-fold, compared with the non-methylated complex. No significant difference in activity was observed by altering the chirality of the diaminocyclohexane ligand. The copper complexes demonstrated antibacterial activity against Bacillus subtilis, Staphylococcus aureus, and Escherichia coli; however, high levels of toxicity (30–60 % of death) were observed in the nematode Caenorhabditis elegans. The copper complexes have also been shown to act as DNA nucleases, with the ability to cleave plasmid DNA in the presence of hydrogen peroxide. The palladium complexes all have half maximal inhibitory concentration (IC50) values of ~10 μM in the L1210 cell line, with no significant difference in the cytotoxicity of any of the compounds tested. Minimal antibacterial activity of the palladium complexes was observed.

Novel Fluorinated 8-Hydroxyquinoline Based Metal Ionophores for Exploring the Metal Hypothesis of Alzheimer’s Disease

Zinc, copper, and iron ions are involved in amyloid-beta (Aβ) deposition and stabilization in Alzheimers disease (AD). Consequently, metal binding agents that prevent metal-Aβ interaction and lead to the dissolution of Aβ deposits have become well sought therapeutic and diagnostic targets. However, direct intervention between diseases and metal abnormalities has been challenging and is partially attributed to the lack of a suitable agent to determine and modify metal concentration and distribution in vivo. In the search of metal ionophores, we have identified several promising chemical entities by strategic fluorination of 8-hydroxyquinoline drugs, clioquinol, and PBT2. Compounds 15-17 and 28-30 showed exceptional metal ionophore ability (6-40-fold increase of copper uptake and >2-fold increase of zinc uptake) and inhibition of zinc induced Aβ oligomerization (EC50s < ∼5 μM). These compounds are suitable for further development as drug candidates and/or positron emission tomography (PET) biomarkers if radiolabeled with (18)F.

Drug Delivery Devices and Targeting Agents for Platinum(II) Anticancer Complexes

An ideal platinum-based delivery device would be one that selectively targets cancerous cells, can be systemically delivered, and is non-toxic to normal cells. It would be beneficial to provide drug delivery devices for platinum-based anticancer agents that exhibit high drug transport capacity, good water solubility, stability during storage, reduced toxicity, and enhanced anticancer activity in vivo. However, the challenges for developing drug delivery devices include carrier stability in vivo, the method by which extracellular or intracellular drug release is achieved, overcoming the various mechanisms of cell resistance to drugs, controlled drug release to cancer cells, and platinum drug bioavailability. There are many potential candidates under investigation including cucurbit[n]urils, cyclodextrins, calix[n]arenes, and dendrimers, with the most promising being those that are synthetically adaptable enough to attach to targeting agents.

Mild Conditions for Deuteration of Primary and Secondary Arylamines for the Synthesis of Deuterated Optoelectronic Organic Molecules

Deuterated arylamines demonstrate great potential for use in optoelectronic devices, but their widespread utility requires a method for large-scale synthesis. The incorporation of these deuterated materials into optoelectronic devices also provides the opportunity for studies of the functioning device using neutron reflectometry based on the difference in the scattering length density between protonated and deuterated compounds. Here we report mild deuteration conditions utilising standard laboratory glassware for the deuteration of: diphenylamine, N-phenylnaphthylamine, N-phenyl-o-phenylenediamine and 1-naphthylamine (via H/D exchange in D2O at 80 °C, catalysed by Pt/C and Pd/C). These conditions were not successful in the deuteration of triphenylamine or N,N-dimethylaniline, suggesting that these mild conditions are not suitable for the deuteration of tertiary arylamines, but are likely to be applicable for the deuteration of other primary and secondary arylamines. The deuterated arylamines can then be used for synthesis of larger organic molecules or polymers with optoelectronic applications.

A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis

Thirteen compounds in a new class of fluorinated 5-pyrrolidinylsulfonyl isatin derivatives were synthesised that have potent and selective inhibitory activity against effector caspases-3 and -7. With in vivo animal PET imaging studies of cerebral ischemia being planned, N-benzylation with selected para-substituted benzylic halides allowed systematic variation of lipophilicity (logP 1.94–3.31) without decreasing inhibition potency (IC50). From this series the p-methoxybenzyl analogue was selected for initial ‘proof-of-concept’ [18F]-fluoride radiolabelling which proceeded in good yield and purity with no need for a protection/deprotection strategy.

Synthesis of 1,4-triazole linked zanamivir dimers as highly potent inhibitors of influenza A and B

The copper catalyzed azide alkyne cycloaddition (CuAAC) reaction – the quintessential ‘click’ reaction – was used to synthesise dimers of the neuraminidase inhibitor zanamivir in high yields. The effect upon anti-viral activity of varying the linker length and the number of triazole units was explored. All dimers were tested for anti-viral activity against influenza A/Sydney/5/97 and B/Harbin/7/94 in a cytopathic effect (CPE) assay.