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Journal ArticleDOI

Bioorganometallic chemistry—from teaching paradigms to medicinal applications

26 Jan 2009-Chemical Society Reviews (The Royal Society of Chemistry)-Vol. 38, Iss: 2, pp 391-401
TL;DR: In this tutorial review, various aspects of bioorganometallic chemistry are introduced, with the main emphasis on medicinal organometallic compounds, and rational ligand design has been shown.
Abstract: In undergraduate level organometallic chemistry courses students are usually taught that organometallic compounds are toxic and unstable in air and water. While this is true of many complexes, some are also non-toxic and stable in air and water. Indeed, bioorganometallic chemistry, the study of biomolecules or biologically active molecules that contain at least one carbon directly bound to a metal, is a thriving subject, and air and water stability is a general pre-requisite. This interdisciplinary field is located at the borderline between chemistry, biochemistry, biology and medicine. In this tutorial review, various aspects of bioorganometallic chemistry are introduced, with the main emphasis on medicinal organometallic compounds. Organometallic therapeutics for cancer, HIV and malaria and other medicinal applications are described. It is also shown how rational ligand design has led to new improved therapies much in the same way that an organometallic chemist working in catalysis will design new ligands for improved activities.
Citations
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Journal ArticleDOI
TL;DR: The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed, and organometallic compounds have recently been found to be promising anticancer drug candidates.
Abstract: The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure ​Figure11 for an overview of these typical classes of organometallics). Figure 1 Summary of the typical classes of organometallic compounds used in medicinal chemistry. In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)

1,364 citations

Journal ArticleDOI
TL;DR: Inorganic compounds should not be overlooked in the realm of chemical biology, since their distinctive electronic, chemical, and photophysical properties render them particularly useful for a variety of applications.
Abstract: Our desire to understand how the individual molecules that make up cells organize, interact, and communicate to form living systems has lead to the burgeoning field of chemical biology, an interfacial area of science that combines aspects of chemistry — the study of matter and its transformations, and biology — the study of living things and their interactions with the environment. The defining feature of chemical biology is the use of chemical approaches and small molecules to interrogate or manipulate biology.1,2 These small molecules are synthetic or naturally occurring ones that, for example, bind to DNA to affect protein expression levels, bind to proteins to inhibit their function, interact with lipids to alter membrane integrity, or become fluorescent in response to a metabolic event. Because small molecules can affect biochemical function, there is a clear link between chemical biology and pharmacology and medicine.3 While small molecules are usually implied as being organic compounds,4 inorganic small molecules also have a long history in both biology and medicine. Ancient civilizations used gold and copper for healing purposes, and the modern era of drug discovery was ushered in when arsenic-containing salvarsan was discovered as an anti-syphilis agent to become the world’s first blockbuster drug.5 Inorganic compounds should therefore not be overlooked in the realm of chemical biology, since their distinctive electronic, chemical, and photophysical properties render them particularly useful for a variety of applications.6-8 What are the properties of metal ions that impart utility to biology? Because inorganic elements comprise the bulk of the periodic table, the diversity of these properties is likewise broad and has been thoroughly covered by several books in the field of bioinorganic chemistry.9-11 A brief summary of the general chemical properties of metals is given below. Charge. Metal ions are positively charged in aqueous solution, but that charge can be manipulated depending on the coordination environment so that a metal complexed by ligands can be cationic, anionic, or neutral. Interactions with ligands. Metal ions bind to ligands (both organic and inorganic) via interactions that are often strong and selective. The ligands impart their own functionality and can tune properties of the overall complex that are unique from those of the individual ligand or metal. The thermodynamic and kinetic properties of metal—ligand interactions influence ligand exchange reactions. Structure and bonding. Metal—ligand complexes span a range of coordination geometries that give them unique shapes compared to organic molecules. The bond lengths, bond angles, and number of coordination sites can vary depending on the metal and its oxidation state. Lewis acid character. Metal ions with high electron affinity can significantly polarize groups that are coordinated to them, facilitating hydrolysis reactions. Partially filled d-shell. For the transition metals, the variable number of electrons in the d-shell orbitals (or f-shell for lanthanides) imparts interesting electronic and magnetic properties to transition metal complexes. Redox activity. Coupled with the variability of electrons in the d-shell is the ability for many transition metals to undergo 1-electron oxidation and reduction reactions. Biology has taken advantage of these chemical properties of metals to perform several functional roles, which are summarized in Table 1. This is by no means an exhaustive list, but rather a primer to highlight important themes. Some metal ions, particularly the alkali and alkaline earth metals, are stable in aqueous solution as cations, making Na+, K+ and Ca2+ ideal for maintaining charge balance and electrical conductivity.10 On the other hand, the distinct architectures accessible via metal—ligand bonding interactions impart important structural roles to metal ions that encompass both macroscopic structural stabilization, as in biomineralized tissues,12 as well as molecular structural stabilization, as in proteins and nucleic acids that are stabilized in a preferred fold by metal ions.13-16 Metal—ligand bonding is also significant in its reversibility. For example, Nature takes advantage of reversible binding of metal ions like Ca2+ and Zn2+ to proteins or other storage repositories in order to propagate various biochemical signals.13,17 Metal ions themselves can be their own signal to adjust DNA transcription, as in the case of metalloregulatory proteins.18,19 Reversible metal—ligand coordination is also exploited to bind and release molecules to and from a metal center, a prime example being O2 binding and release from hemoglobin. Table 1 Functional roles of inorganic elements found in biology, with selected representative examples.

713 citations

01 Jan 2008
TL;DR: The recent achievement of oxaliplatin for the treatment of colon cancer should not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs.
Abstract: Triggered by the resounding success of cisplatin, the past decades have seen tremendous efforts to produce clinically beneficial analogues. The recent achievement of oxaliplatin for the treatment of colon cancer should, however, not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs. Strategies opening up new avenues are increasingly being sought using complexes of metals other than platinum such as ruthenium or gallium. Based on the chemical differences between these metals, the spectrum of molecular mechanisms of action and potential indications can be broadened substantially. Other approaches focus on complexes with tumour-targeting properties, thereby maximizing the impact on cancer cells and minimizing the problem of adverse side effects, and complexes with biologically active ligands.

698 citations

Journal ArticleDOI
TL;DR: This review describes the advances that have been achieved in using transition metal complexes containing NHC ligands as antitumor agents and clearly demonstrate the great potential of metal-NHC complexes as antitUMor agents.
Abstract: The discovery of cisplatin's antitumor activity in 1969 prompted the search for novel metal-containing complexes as potential anticancer drugs. Among these novel complexes, metal N-heterocyclic carbene (NHC) complexes have recently gained considerable attention because they perfectly fit prerequisites for efficient drug design and fast optimization. Moreover, most of them have shown higher cytotoxicity than cisplatin. This review describes the advances that have been achieved in using transition metal (Ag, Au, Pt, Pd, Cu, Ni, and Ru) complexes containing NHC ligands as antitumor agents. Their modes of action at the cellular lever are further discussed. All these initial achievements clearly demonstrate the great potential of metal–NHC complexes as antitumor agents.

637 citations

Journal ArticleDOI
TL;DR: Neutral or cationic arene ruthenium complexes providing both hydrophilic as well as hydrophobic properties due to the robustness of the rUThenium-arene unit hold a high potential for the development of metal-based anticancer drugs.
Abstract: Neutral or cationic arene ruthenium complexes providing both hydrophilic as well as hydrophobic properties due to the robustness of the ruthenium–arene unit hold a high potential for the development of metal-based anticancer drugs. Mononuclear arene ruthenium complexes containing P- or N-donor ligands or N,N-, N,O- or O,O-chelating ligands, dinuclear arene ruthenium systems with adjustable organic linkers, trinuclear arene ruthenium clusters containing an oxo cap, tetranuclear arene ruthenium porphyrin derivatives that are photoactive, as well as hexanuclear ruthenium cages that are either empty or filled with other molecules have been shown to be active against a variety of cancer cells.

554 citations

References
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Journal ArticleDOI
TL;DR: The preclinical and early clinical development of KP1019 - from bench to bedside - is recapitulated and promising activity against certain types of tumors is observed.

875 citations

Journal ArticleDOI
TL;DR: The recent achievement of oxaliplatin for the treatment of colon cancer should not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs as discussed by the authors.
Abstract: Triggered by the resounding success of cisplatin, the past decades have seen tremendous efforts to produce clinically beneficial analogues. The recent achievement of oxaliplatin for the treatment of colon cancer should, however, not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs. Strategies opening up new avenues are increasingly being sought using complexes of metals other than platinum such as ruthenium or gallium. Based on the chemical differences between these metals, the spectrum of molecular mechanisms of action and potential indications can be broadened substantially. Other approaches focus on complexes with tumour-targeting properties, thereby maximizing the impact on cancer cells and minimizing the problem of adverse side effects, and complexes with biologically active ligands.

729 citations

Journal ArticleDOI
TL;DR: What the future holds for metal-based drugs, in particular anti-metastasis drugs,In these enlightened times of the post genomic era is discussed.
Abstract: The discovery of new metal-based antitumour drugs, whether cisplatin derivatives or those based on other metals, has been largely based on cell viability assays (IC50 values) and compounds that bind to DNA. This approach has been applied for more than 30 years during which time very few new drugs have entered clinical use. In this article we discuss what the future holds for metal-based drugs, in particular anti-metastasis drugs, in these enlightened times of the post genomic era.

702 citations