Trevor W. Hambley

Platinum(IV) antitumour compounds: their bioinorganic chemistry

This article reviews the investigations undertaken into platinum(IV) antitumour compounds since Barnett Rosenberg first noted the activity of platinum(IV) complexes. The chemical and pharmacological properties of the drugs are discussed and both the reactions with individual biomolecules, which have received attention and the characterisation of biotransformation products from animal and clinical trials are reviewed. The bioinorganic chemistry of platinum(IV) complexes has not previously been reviewed, and the purpose here is to provide insight into the requirements for the antitumour activity of platinum(IV) complexes.

Copper complexes of non-steroidal anti-inflammatory drugs: an opportunity yet to be realized

The proposed curative properties of Cu-based non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous Cu(II) complexes of NSAIDs with enhanced anti-inflammatory activity and reduced gastrointestinal (GI) toxicity compared with their uncomplexed parent drug. These low toxicity Cu drugs have yet to reach an extended human market, but are of enormous interest, because many of todays anti-inflammatory drug therapies, including those based on the NSAIDs, remain either largely inadequate and/or are associated with problematic renal, GI and cardiovascular side effects. The origins of the anti-inflammatory and gastric-sparing actions of Cu-NSAIDs, however, remain uncertain. Their ability to influence copper metabolism has been a matter of debate and, apart from their frequently reported superoxide dismutase (SOD)-like activity in vitro, relatively little is known about how they ultimately regulate the inflammatory process and/or immune system. Furthermore, little is known of their pharmacokinetic and biodistribution profile in both humans and animals, stability in biological media and pharmaceutical formulations, or the relative potency/efficacy of the Cu(II) monomeric versus Cu(II) dimeric complexes. The following review will not only discuss the etiology of inflammation, factors influencing the metabolism of copper and historical overview of the development of the Cu-NSAIDs, but also outline the structural characteristics, medicinal and veterinary properties, and proposed modes of action of the Cu-NSAIDs. It will also compare the SOD, anti-inflammatory and ulcerogenic effects of various Cu-NSAIDs. If the potential opportunities of the Cu-NSAIDs are to be completely realized, a mechanistic understanding and delineation of their in vivo and in vitro pharmacological activity is fundamental, along with further characterization of their pharmacokinetic/pharmacodynamic disposition.

The influence of structure on the activity and toxicity of Pt anti-cancer drugs

Abstract The development and current status of the relationships between the structure of platinum based anti-cancer drugs and their biological activities are reviewed. The early structure-activity relationships contributed to the development of many other active compounds and to the development of the understanding of the mechanism of activity of this class of drugs. However, they may also have contributed to the focusing on a group of compounds that has yet to produce a major advance over cisplatin or carboplatin. The recent development of new highly active platinum based drugs that do not fit the structure-activity rules indicates the need for a reappraisal of these rules. Some new structure-activity relationships are emerging but we conclude that in general it is unlikely that widely applicable rules will be sustained or be useful. We also review the results of our recent work aimed at rationally probing the relationships between structure and activity. We describe studies aimed at determining why cisplatin does not bind to GpA sequences of duplex DNA and determining whether the GG interstrand adduct contributes to anti-cancer activity. Chiral probes of Pt/DNA interactions, cytotoxicity and other toxicities are also described. Stereoselective interactions between Pt complexes and DNA arc described and the factors contributing to the stereoselectivity arc discussed.

Platinum Drug Distribution in Cancer Cells and Tumors

The era of platinum-based anticancer drugs was heralded by the clinical introduction of cisplatin (1), a square-planar platinum(II) complex whose antitumor properties were first reported by Rosenberg in 1969.1 The success of cisplatin paved the way for the secondand third-generation platinum(II) drugs, carboplatin (2) and oxaliplatin (3), while the platinum(IV) complex satraplatin (4) has recently undergone phase III trials and was considered for FDA approval.2 Platinum drugs continue to play a central role in the treatment of cancer and are used in the chemotherapeutic regimes of around half of all cancer patients.3,4 The search for new platinum anticancer drugs is driven by the need to overcome the side effects and limited tumor penetration of existing platinum agents, as well as intrinsic and acquired resistance. To achieve such advances, an understanding of the mechanisms by which tumors and cells distribute and process platinum drugs is crucial. A comprehensive understanding of the cellular processing of platinum drugs remains elusive, with often seemingly contradictory reports appearing in the literature. For example, the relative contributions of passive diffusion, and active and facilitated transport to the cellular uptake, and accumulation of platinum drugs have generated an ongoing debate, while the existence of an active efflux mechanism is also a contentious topic and both have been the subject of recent and extensive review.5 [It should be noted that “uptake” and “accumulation” are distinct terms. Accumulation is a steady-state phenomenon resulting from simultaneous influx and efflux of platinum and, thus, refers to the cellular platinum concentration at any given point in time. Consequently, it is a property that can be measured quantitatively. Uptake, conversely, is the dynamic process * Corresponding author. E-mail: t.hambley@chem.usyd.edu.au. Phone: 612-9351-2830. Fax: 61-2-9351-3329. Alice Klein obtained her undergraduate Chemistry degree at the University of Sydney in 2008, completing an Honours project on the subject of platinum anticancer complexes. She is now undertaking a Ph.D. at the University of Sydney and is pursuing her interest in platinum chemistry under the supervision of Professor Trevor Hambley. In particular, her research focuses on developing novel platinum(IV)-intercalator hybrid complexes and investigating their potential as antitumour agents in cells.

Is Anticancer Drug Development Heading in the Right Direction

The success of molecularly targeted agents, such as imatinib, has led to expectations of a new era in anticancer drug development, and to a greatly increased focus on targeting as a strategy. However, the number of successes to date is small, and recent results suggest that the success of imatinib, for instance, in treating chronic myelogenous leukemia and gastrointestinal stromal tumor may be the exception rather than the rule. Here, we argue that the search for new anticancer agents needs to continue on as many fronts as possible, and not be focused on one strategy alone.

Cycloxazoline : a cytotoxic cyclic hexapeptide from the ascidian Lissoclinum bistratum

Abstract The isolation of a new cyclic hexapeptide is reported from a marine ascidian Lissoclinum bistratum. The structure was determined by NMR, mass spectrometry and X-ray crystallographic techniques. Cytotoxicity against MRC5CV1 and T24 cells expressed as IC50 was 0.5 μg/mL.

Organolanthanoids V. The crystal and molecular structure of DI-η5-cyclopentadienyl-1,2-dimethoxyethaneytterbium(II)

Abstract Crystals of di-η5-cyclopentadienyl-1,2-dimethoxyethaneytterbium(II) are mono-clinic, space group Cc, with a 9.25(2), b 23.49(5), c 8.23(2) A, β 123.59(4)° and Z  4. The ytterbium ion is pseudo-tetrahedrally coordinated by two cyclopentadienyl groups and a bidentate 1,2-dimethoxyethane ligand, and there is no inter-molecular association. The sites of the cyclopentadienyl ligands are disordered.

Preparation and characterization of dinuclear copper–indomethacin anti-inflammatory drugs

Abstract The crystal and molecular structures of the ternary copper–indomethacin complexes [Cu2(Indo)4L2] (IndoH=indomethacin=1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid; L=acetonitrile (AN), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), or pyridine (Py)) are reported. All four complexes contain a dinuclear ‘Cu-acetate’ molecular structure in which the carboxyl groups of the indomethacin ligands act as bridges. The CuCu distances of 2.649(3), 2.6240(8), and 2.6784(8) A; CuO(Ac)av distances of 1.964, 1.970, and 1.967 A; and CuL distances of 2.132(6), 2.1805(17), and 2.177(2) A, respectively, for L=DMA, THF and Py, are typical of such distances in dinuclear complexes of this type. There are two independent complexes in the AN adduct with CuCu distances of 2.6311(11) and 2.6206(8) A; CuO(Ac)av distances of 1.965 and 1.965 A; and CuLav distances of 2.184 and 2.197 A, respectively. The pyridine complex exists mainly as a monomer in solution, which may be associated with the longer CuCu bond in this adduct as compared to the other complexes.

Modifying the properties of platinum(IV) complexes in order to increase biological effectiveness

The preparation of a series of novel Pt(IV) complexes containing the anionic polyfluoroaryl ligands, 2,3,5,6-tetrafluorophenyl (p-HC6F4), 2,3,5,6-tetrafluoro-4-methoxyphenyl (p-MeOC6F4) and pentafluorophenyl (C6F5) are described. The crystal structure of a representative complex, [Pt(p-MeOC6F4)2(O2CEt)2(en)] (en = ethane-1,2-diamine) was determined and confirms the trans arrangement of the carboxylato ligands. Reduction potentials of the series of complexes reveal that replacement of equatorial chloro ligands by polyfluoroaryl ligands makes reduction substantially more difficult. They also confirm previously reported trends in that complexes having axial carboxylato ligands are more readily reduced than those having axial hydroxo ligands. Reduction potentials and in vitro activities showed no obvious correlations. Moderate to high activity was observed for many complexes in the series, including some of those that were very difficult to reduce.

Porphyrin analogues of Tröger's base: large chiral cavities with a bimetallic binding site

2-Amino-5,10,15,20-tetraarylporphyrins react with formaldehyde to give good yields of the corresponding octaaryl derivatives of the Trogers base analogue in which two porphyrins are covalently Jinked by a diazocine bridge; the X-ray crystal-structure of the bis(tetraphenylporphyrinato)dipalladium(II) derivative 6 reveals a concave chiral cavity with two metal ion binding sites suitable for ditopic interactions with guest molecules.