Application of Metal Coordination Chemistry to Explore and Manipulate Cell Biology

By Kathryn L. Haas, K. Franz. Chemical Reviews, 2009

868 citations recorded by the source corpus.

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. The reactivity of metallic centers in biology rests mostly in their Lewis acid or redox-active characters. Metal centers that are strong Lewis acids can activate coordinated ligands for reactivity, so for example a water molecule coordinated to a Zn(II) center becomes a potent nucleophile for amide bond hydrolysis of a protein substrate.20 In terms of redox activity, a wide variety of transition metals that can access variable oxidation states are found incorporated as enzyme cofactors to carry out oxidation/reduction chemistry. Electron transfer units like cytochromes, iron-sulfur clusters, and blue copper proteins shuttle electrons to other proteins that require redox chemistry for their function, while other redox proteins catalyze multielectron oxidation/reduction reactions directly on a substrate. Examples here involve oxygen metabolism, including the reduction of dioxygen to water by cytochrome c oxidase, and hydrocarbon oxidation catalyzed by cytochrome P-450 enzymes, to name just a few. When it comes to applying inorganic compounds to biology, chemists are not restricted to the naturally bioavailable set of metals and can take advantage of the properties of biologically exotic elements, including 2nd and 3rd row transition elements and the lanthanide (Ln) elements. This expansion leads to the list of functional roles of inorganic elements applied to biology shown in Table 2. Many of the functions listed in Table 2 mirror those of Table 1, but applied in novel ways. For example, the structures of kinetically inert metal complexes are found to interact with proteins and nucleic acids in unique ways, and the acid-base and redox activity of native and non-native metals can be harnessed for artificial reactivity. Metal complexes can also impart additional functionality not found naturally. The most striking addition to the list is in visualization, where the photophysical, magnetic, and radioactive properties of metals make possible studies based on luminescence, magnetic resonance, PET, and SPECT imaging modalities. Table 2 Functional roles of inorganic elements applied to biology, with selected representative examples and reference to the relevant section of this article. This review will explore how the properties of inorganic coordination complexes are applied in the context of inorganic chemical biology, with a particular focus on applications related to cellular trafficking and regulation. We will delve into the structure, bonding, spectroscopy, and reactivity of transition metal coordination compounds and explore how their unique properties can be used as probes and tools to understand or control biological processes. Our discussion will expand on the functions and examples listed in Table 2, which is really only a partial list, as the examples of inorganic and organometallic complexes applied to biology continue to grow. Our focus is on compounds used in cells to understand the trafficking or regulation of something, be it the metal itself or some other molecule or process that is enabled or visualized by a metal complex. Many of the compounds that are discussed have potential applications in medicine, but the reader is referred to other excellent sources for implicit coverage of medicinal and diagnostic uses of metal complexes.24-33 There have been significant advances in the development of fluorescent probes for monitoring cellular metals. Such molecules are clearly important tools in inorganic chemical biology but will not be covered here, as there are several excellent reviews available.34-39 We define a metal complex that is a “probe for biological systems” as one that can be used in ways to teach us about the chemical biology of living cells. It may be used in vivo or in vitro with the aim of understanding how cells operate. With this definition in mind, we will discuss metal chelators and metal complexes that are being used or have potential to be used to this end, with an emphasis on those that are applied in cellular studies.

Subfields: Inorganic Chemistry, Oncology, Spectroscopy

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