Current Topics in Medicinal Chemistry - Volume 12, Issue 3, 2012

Metal based agents are continuously gaining increasing attention as potential drug candidates or as tools in diagnostic applications. Combination of unique intrinsic properties of metal ions and complexes, e.g. redox-properties, radioactivity, magnetism or reactivity, with the multiplicity of various organic and bioorganic ligands afforded an inconceivable number of potential molecules. The known activities of several metal ions in biology have stimulated further developments of metal-based therapeutics and diagnostics. The present issue of Current Topics in Medicinal Chemistry deals with some of the unique aspects associated with recent results regarding the therapeutic and diagnostic potential of metal based agents. First of all, the ligands employed for metal ion coordination play an integral role in tailoring the resulting agent for specific application, allowing for fine tuning of important drug parameters. Besides the classical ligand design aiming for optimized complex formation, metal binding, complex stability, water solubility, overall charge, secretion pathway, complex dissociation and related toxicity, recent research has centered on including added functionalities to ligands. With this approach multifunctional ligands with enhanced targeting, reporting and overall efficacy have been developed. A comprehensive overview of new developments of such multifunctional ligands and their application is given by Tim Storr and co-workers (Simon Fraser University, Canada). Introduction of biologically derived functionalities onto metal based agents in order to use specific binding or transport phenomena is currently widely studied for the design of novel drugs and diagnostics. Among others, much effort has been spend to conjugate carbohydrates to various metal complexes. Sugars are key-substances in many biological events, e.g. transport and recognition processes. Recent attempts for the synthesis of sugar-based metal complexes are discussed by S. Yano & Y. Mikata (Kyoto University and Nara Women' University, Japan) with special emphasis on palladium complexes, the synthesis of Cglycosides, C-glycoside-amino acid hybrid molecules, sugar-dipicolylamine conjugates as well as introduction of oligosaccharides to photofunctional porphyrine derived molecules. From the view of the constitutive basic ligand system certainly oligopyridines as well as porphyrines have achieved major impact on current developments of metal based agents. This is due to the often unique photophysical properties of their metal complexes. Therefore, a major part of the issue will focus on or at least deal with polypyridyl-derived metal complexes from different points of view, e.g. the type of polypyridyl ligands used, photophysical or toxicological properties, interaction with biomolecules or focused on particular metal centers. One of the widespread groups of polypyridyl metal complexes is derived from terpyridine. So far, the majority of results for biomedical application of these types of complexes were published for heavy second or third row transition metal ions (like PtII and RuIII complexes as anti tumor agents and IrIII, PtII and EuIII for biolabeling). In recent years terpyridine based complexes from first row transition metals, which are naturally more abundant and intrinsically less toxic, have been reported to possess biological activities as, e.g., anti tumor agents or DNA oxidants. The review from Winter and co-workers (Friedrich-Schiller- University of Jena, Germany) emphasizes developments in this particular area. The current status of functional terpyridines and terpyridine-like ligands and their complexes with Zn, Cu, Fe, Cr, Co and V in different oxidation states is presented and their cytotoxic and nuclease activities as well as their properties in terms of labeling biomolecules and in self-assembly processes is evaluated.....

This review will highlight recent advances in ligand design for innovative applications in medicinal inorganic chemistry. Ligands that effectively bind metal ions and also include specific features to enhance targeting, reporting, and overall efficacy are driving innovation in areas of disease diagnosis and therapy. Increasing the potency of therapeutic compounds, while limiting side-effects, is a common goal in medicinal chemistry. In an effort to achieve this goal, compounds are being developed that either target a disease site, or are activated by a disease specific biological process. Metal complexes containing targeting functions and/or bioactive ligands, as well as agents that are activated by specific enzymes, or changes in pH and pO2, provide new avenues for drug development. Radiodiagnostic compounds, magnetic resonance imaging agents, and optical probes containing transition metals offer versatility unavailable to organic imaging agents. In certain cases, dual modality agents have been developed, and will be highlighted. Finally, we will discuss targeted metal binding compounds for treatment of metal overload disorders, and the recent application to neurodegenerative disease.

Recent progresses of our group dealing with newly developed sugar-based ligands and their metal complexes have been reviewed. Carbohydrate moiety affects on the stereochemistry around the metal center and controls the biological activity of the complex.

Transition metal complexes with terpyridine ligands have attracted a widespread interest with respect to biomedical applications: [(tpy)PtCl]Cl and [(tpy)RuCl3] are potent anti-tumor agents with activities comparable to those of cisplatin and carboplatin. The RuII complexes feature a high potential as reactive probes for DNA oxidation; whereas, luminescent IrIII, PtII or EuIII complexes have been utilized in biolabeling applications. Besides complexes based on heavy second or third row transition metal ions, remarkable results have been obtained with respect to the development of new types of metallodrugs, based on the naturally more abundant and intrinsically less toxic first row transition metal ions (e.g. FeII, CuI/II, ZnII). The perspective of these complexes in particular with respect to future biomedical applications in chemotherapy and cleavage of nucleic acids is evaluated in this review.

Photodynamic therapy (PDT) and photodynamic diagnosis of cancer are widely used in clinical fields. These are performed using photosensitizers. Many metalloporphyrin-related compounds have been developed as photosensitizers for use in PDT, and these tumor localization ability have been improved in recent research. Moreover, the precursor of porphyrin 5-aminolevulinic acid is used in fluorescence diagnosis using its tumor localization ability. In this review, these applications of photosensitizers in cancer therapy and diagnosis are summarized.

Since the discovery of cisplatin, the search for diagnostic or therapeutic agents based on other metals, has expanded intensively owing to the numerous possibilities offered by coordination chemistry. This mini-review focuses on recent advances in the search for RuII polyazaaromatic complexes of potential interest as molecular tools applied to cellular diagnostics or as specific cellular photo-reagents for future biomedical applications. The interaction of RuII polyazaaromatic complexes with living cells is reported, as well as the photo-reaction mechanisms of photo-oxidizing RuII complexes with nucleic acids. The novel strategies currently developed to improve their reactivity and specificity towards DNA, more particularly in the gene-silencing framework, are also discussed.

Transition metal complexes with oligopyridine ligands and ruthenium or rhenium centers have attracted a widespread interest with respect to biomedical applications as they are luminescent and form triplet excited states which may form 1O2. These complexes have been shown to enter living cells and even cellular nuclei. In addition detailed investigations of their interaction with proteins/enzymes have shown that they are capable of binding to these biomolecules, alter the redox state of the enzyme metal centre and induce different reactivity. The application of these complexes as photoactive metallodrugs will depend on their photophysical and photochemical properties. The potential of these complexes together with relevant aspects of their chemistry will be discussed in this review.

Biological trace metals such as iron, zinc, copper, and manganese are essential to life and health of humans, and the success of platinum drugs in the cancer chemotherapy has rapidly grown interest in developing inorganic pharmaceutical agents in medicinal chemistry, that is, medicinal inorganic chemistry, using essential elements and other biological trace metals. Transition metal complexes with unique chemical structures may be useful alternatives to the drugs available to address some of the incurable diseases. In this review, we emphasize that metal complexes are an expanding of interest in the research field of treatment of diabetes mellitus. Especially, orally active anti-diabetic and anti-metabolic syndrome zinc complexes have been developed and progressed since the discovery in 2001, where several highly potent anti-diabetic zinc complexes with different coordination structures have quite recently been disclosed, using experimental diabetic animals. In all of the complexes discussed, zinc is found to be biologically active and function by interacting with some target proteins related with diabetes mellitus. The design and screening of zinc complexes with higher activity is not efficient without consideration of the translational research. For the development of a clinically useful metallopharmaceutics, the research of zinc complexes on the long-term toxicity including side effects, clear-cut evidence of target molecule for the in vivo pharmacological action, and good pharmacokinetic property are essential in the current and future studies.

More than 99% of currently approved clinical drugs are organic compounds. In contrast, the percentage of metal-containing drugs (metallodrugs) is very low. In cancer chemotherapy, however, platinum coordination compounds represented by cisplatin and derivatives thereof are essential anticancer agents with proven effects against a variety of tumors. Because of the proven clinical applications of these platinum-based drugs, the number of research initiatives to identify other metallodrugs that can be used for cancer therapy has increased considerably in the field of inorganic biochemistry. Anticancer platinum compounds continue to be designed and synthesized through several different approaches in order to improve the therapeutic effects and to overcome the disadvantages of current platinum-based drugs. The use of transition metal compounds other than platinum has also attracted attention. Gold coordination complexes, for instance, demonstrate outstanding cytotoxic properties, and certain ruthenium complexes possess a strong ability to inhibit metastases of solid invasive tumors. In this review, the potential of anticancer metallodrugs is described and representative examples from the most recent families of Pt-, Ru-, and Au-based compounds are discussed with respect to their possible modes of action and most probable biomolecular targets.