New trends for metal complexes with anticancer activity

doi:10.1016/j.cbpa.2007.11.013

Current Opinion in Chemical Biology

Volume 12, Issue 2, April 2008, Pages 197-206

https://doi.org/10.1016/j.cbpa.2007.11.013 Get rights and content

Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side-effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selective delivery and/or activation of cisplatin-related prodrugs and the discovery of new non-covalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in ‘metals in medicine’.

Introduction

Medicinal inorganic chemistry [1••, 2, 3] is a field of increasing prominence as metal-based compounds offer possibilities for the design of therapeutic agents not readily available to organic compounds. The wide range of coordination numbers and geometries, accessible redox states, thermodynamic and kinetic characteristics, and the intrinsic properties of the cationic metal ion and ligand itself offer the medicinal chemist a wide spectrum of reactivities that can be exploited. Although metals have long been used for medicinal purposes in a more or less empirical fashion [4], the potential of metal-based anticancer agents has only been fully realised and explored since the landmark discovery of the biological activity of cisplatin [5]. To date, this prototypical anticancer drug remains one of the most effective chemotherapeutic agents in clinical use. It is particularly active against testicular cancer and, if tumours are discovered early, an impressive cure rate of nearly 100% is achieved. The clinical use of cisplatin against this and other malignancies is, however, severely limited by dose-limiting side-effects such as neuro-, hepato- and nephrotoxicity [5]. In addition to the high systemic toxicity, inherent or acquired resistance is a second problem often associated with platinum-based drugs, which further limits their clinical use. Much effort has been devoted to the development of new platinum drugs and the elucidation of cellular responses to them to alleviate these limitations [5, 6]. These problems have also prompted chemists to develop alternative strategies based on different metals and aimed at different targets. We summarize here recent activities in the field of metal-based anticancer drugs. This overview highlights some significant recent advances and illustrates emerging trends.

Section snippets

New modes of interaction with the classical target, DNA

In classical chemotherapy, anticancer agents target DNA directly according to the cisplatin paradigm to generate lesions which ultimately trigger cell death. Much effort has been directed towards combatting the high systemic toxicity of traditional platinum anticancer agents by designing drug delivery systems capable of delivering platinum to tumour cells only.

A recent example of the latter strategy is the encapsulation of cisplatin and carboplatin in the hollow protein cage of the iron storage

Non-covalent interactions with DNA

Single-stranded ends of human telomeric DNA, which consist of guanine-rich TTAGGG repeats known to fold into G-quadruplex structures (Figure 2a), provide interesting targets for drug design. Telomeric DNA shortens after every cell division and after critical shortening of the telomeres, cells stop dividing and commit suicide. Telomerase, however, maintains the length of the telomeric DNA and overexpression of this enzyme endows the (cancer) cell with the ability to replicate indefinitely and

The metal as scaffold

Metals ions have been traditionally included in anticancer agents to exploit their reactivity and have been particularly attractive because of the exceptionally wide range of reactivities available. On the other hand, metals can also be used as building blocks for well-defined, three-dimensional constructs. In this way, the availability of many different coordination geometries allows for the synthesis of structures with unique stereochemistry and orientation of organic ligands and structures

Proteins and enzymes as non-classical targets

Traditional anticancer drugs that target DNA make use of the fact that malignant cells divide rapidly. A drawback of this strategy is that rapidly dividing healthy cells are affected as well, causing severe toxic side-effects. Alternatively, the design of novel agents that target cellular signalling pathways specific to cancer cells would therefore be preferred. As genomics and proteomics have resulted in an explosion of available information concerning the biology of cancer cells, such

From inorganic to bioorganometallic drugs

The fact that many of the compounds mentioned above are organometallic complexes illustrates the emergence of the field of medicinal organometallic chemistry. More generally, bioorganometallic chemistry is relatively new, but has already led to exciting developments [50]. A prototypical example of a promising organometallic (pro)drug is the now well-established ferrocifen (19, Figure 4e) system. Ferrocifen, in contrast to its parent tamoxifen, is active against both ER(+) and ER(−) human breast

Conclusions

This survey of recent literature illustrates that many different new creative approaches are being taken towards the design of innovative metal-based anticancer drugs. The clinical success of cisplatin remains a stimulus for the development of new complexes that address the downsides associated with cisplatin, especially the systemic toxicity and (acquired) resistance. Targeted delivery and/or controlled prodrug activation, be it by light, intracellular reduction or other means, hold the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

PCAB thanks the Netherlands Organisation for Scientific Research (NWO) for financial support through a Rubicon Scholarship. We thank the EPSRC, BBSRC, Royal Society, Wellcome Trust, EC (Marie Curie and COST), Scottish Enterprise, and Oncosense Ltd. for support of our recent research on therapeutic metal complexes.

The University of Edinburgh (former employer of PJS) has filed patent applications relating to the ruthenium arene and platinum diazido complexes under study in the PJS laboratory.

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View full text

New trends for metal complexes with anticancer activity

Introduction

Section snippets

New modes of interaction with the classical target, DNA

Non-covalent interactions with DNA

The metal as scaffold

Proteins and enzymes as non-classical targets

From inorganic to bioorganometallic drugs

Conclusions

References and recommended reading

Acknowledgements

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