The bio-relevant metals of the periodic table of the elements

2.1 The bulk elements of the s-block

The biological bulk elements sodium, potassium, magnesium, and calcium are highly abundant [4] and essential for all domains of life [5]. These four metals are situated in the s-block of the PTE (see Fig. 1) [5], [6]. They release easily their s electrons and are therefore found in Nature only as stable mono- or dications, respectively, with no potential for redox reactions:

Fig. 1:

Shortened version of the Periodic Table of the Elements indicating those metals which are of relevance for life. [Dark green: s-block metals; light green: essential d metals; yellow: metals essential for some species; Cr and Se are special cases, see text]. Based on information provided in Refs. [5] and [6].

Sodium (Na) and Potassium (K) occur widely in the Earth’s crust; they comprise 2.4% and 2.6%, respectively, of the mineral material, and huge amounts are present in sea water [7]. In aqueous solution the alkali metal ions Na⁺ and K⁺ are to a large part freely available and not fixed in complexes; they are needed to maintain the osmotic balance and to act as counter ions of the multitude of anions and of negatively charged functional groups, e.g. of nucleic acids [4]. Indeed, the sugar-phosphate backbone of nucleic acids is mostly associated with alkali metal ions for charge compensation [4]. In blood plasma the normal concentrations of Na⁺ are in the range of 135–145 mm, and for K⁺ of 3.5–4.5 mm; in contrast, in cellular fluids the concentrations are almost reversed, that is, 10 mm for Na⁺ and 150 mm for K⁺ [8]. However, Na⁺ and especially K⁺ can also be linked to enzymes; for example, dialkylglycine decarboxylase belongs to the pyridoxal phosphate-dependent enzymes, it is activated by K⁺ and inhibited by Na⁺ [9]. A related example is pyruvate kinase, that requires two Mg²⁺ and one K⁺ as inorganic cofactors [9]. Overall, it appears that K⁺ has a somewhat greater role in biology than Na⁺ [9], especially if one considers the G quadruplex structures in which a fully dehydrated K⁺ is bound to the (C6)O carbonyl groups of the guanine residues [4].

Magnesium (Mg) is the second most abundant cellular cation after potassium; it is essential for regulating numerous cellular functions, like enzymes, ion channels, metabolic cycles, and signaling pathways [10]. Therefore, Mg²⁺ homeostasis is important [10], [11]. Hypermagnesemia results in renal failure and hypomagnesemia is connected with cardiovascular pathologies, hypertension, alcoholism, etc., and diabetes induces Mg²⁺ loss. It is estimated that most of Mg²⁺ is bound rather tightly to the widely abundant phosphate groups, e.g. to phospholipids forming the cell wall, the nucleoside triphosphates, and nucleic acids in general [4]. The 30 mm total concentration is thus reduced to just 1–2 mm fully solvated Mg²⁺ in the cell plasma [4]. Many examples are known for Mg²⁺-activated enzymes, especially kinases, sometimes even two Mg²⁺ are needed (or another cation). Commonly Mg²⁺ is bound to the enzyme (amino acid side chains) as well as to the triphosphate residue of a nucleoside triphosphate [12]. It is also worth to note that Mg²⁺ binds well to specific local structures in RNA, e.g. tandem GC base pairs, GU wobble pairs, etc. [4], [13]. A large variety of orally administered magnesium drugs is on the market [14] that are used to cope with any deficiencies resulting from excessive loss of magnesium through sweat in labour, physical exercise and hot climate. Magnesium “complexes” formed with the anions from l-aspartic or citric acid are prominent formulations [14].

Calcium (Ca) is the third most abundant metal (after aluminum and sodium) on Earth [15]. Furthermore, it is part of the most abundant “minerals” in the human body. It is stored in the skeleton in the form of hydroxyapatite, Ca₁₀(PO₄)₆(OH)₂, and it occurs also in teeth as fluoroapatite. Maintenance of this store of Ca²⁺ is important for hindering osteoporosis and other bone maladies and thus, it is relevant for the long-term well-being of an individual [16]. Ca²⁺ is a universal carrier of biological information: It controls cell life from its origin at fertilization to its end in the process of programmed cell death [17]. Evolution has thoroughly exploited the chemical properties of Ca²⁺, that is, its fast ligand-exchange rate and its reversible binding to sites of irregular geometry offered by biological macromolecules, and selected it as a carrier of cellular signals [15]. Ca²⁺ can act as a first messenger by interacting with a plasma membrane receptor to set in motion intracellular signaling pathways (as a neurotransmitter [4]) that involve Ca²⁺ itself [15]. All this is connected with proteins like calmodulin (an EF-hand protein) and S100 proteins as calbindin D9K, calcyclin, and psoriasin [16], others are calreticulin and parvalbumin [17].

For a brief consideration of lithium and strontium see below in Section 2.7.

Beryllium (Be) has long been classified as extremely toxic, but the action is attributed mainly to the irritations of lung tissues by microparticles of insoluble compounds like BeO [18], [19]. For soluble beryllium salts, the effects are still uncertain [19], [20]. By contrast, at the other end of the p-block, Barium (Ba) is also a highly toxic element, but here insoluble barium salts like BaSO₄ are of no risk, whereas soluble barium salts have the adverse effects typical of heavy metal poisoning [21].

2.2 The essential trace elements for humans in the d-block

After having introduced the four essential bulk elements, we now have a look on the essential trace elements for humans. These elements all occur in the d-block and there mostly in the second half of the 3d series (the “late 3d elements”). According to Williams and Fraústo da Silva [5], together with more recent insights of Maret [6], for humans these elements are manganese, iron, cobalt, copper, zinc, and molybdenum, only the last one being a 4d element. All these metal ions play rather diverse roles; a few examples are given for each element:

Manganese (Mn) is the twelfth most abundant element on the planet and occurs in significant amounts in the Earth’s crust [22]; as indicated, it is an essential trace element for humans and incorporated into several metalloproteins like arginase (the rate-limiting enzyme in urea synthesis), phosphoenolpyruvate decarboxylase, and Mn superoxide dismutase, an important enzyme in mitochondria, combatting reactive oxygen species (ROS). There is also an iron superoxide dismutase [23]; furthermore, the devastating mammalian pathogen Staphylococcus aureus owns a superoxide dismutase that is able to function with iron or manganese [24].

Iron (Fe) is a redox-active metal ion which is abundant in the Earth’s crust [25], but at pH 7 Fe³⁺ is by a factor of about 1000 less soluble than Fe²⁺ [4]; this fact has played a key role in evolution [25]. In this context it is interesting to note that pyrite formation (FeS₂) from FeS and H₂S at ambient temperature is mediated through microbial redox activity, as described very recently [26]. This is a reaction postulated to have operated as an early form of energy metabolism on primordial Earth [26]. Clearly, iron is an essential element, but its level needs to be carefully controlled in all organisms [23], [25]. More than 500 human metalloproteins contain iron [25]; many have either a heme prostethic group [23], [25] or an iron-sulfur cluster [25]. Interestingly, the majority of sulfite (SO₃²⁻) reductases (which lead to S²⁻ in a six-electron reduction) are metalloenzymes that use an iron-containing porphyrinoid called siroheme that is covalently linked to a [4Fe-4S] cluster via a shared cysteine ligand [27]. These siroheme-dependent sulfite reductases are homologous to a large class of siroheme-dependent nitrite reductases which catalyze the also six-electron reduction NO₂⁻→NH₃ [27]. The sulfite reductases have inspired Lu et al. [28] to design an artificial enzyme based on a heme-[4Fe-4S] cofactor in cytochrome c peroxidase as a structural and functional model of the enzyme sulfite reductase. The initial model was improved through rational tuning of the secondary sphere interactions around the [4Fe-4S] unit. This ingenious study [28], [29] of a six-electron, seven-proton reaction provides strategies for designing highly active multifactor artificial enzymes.

Cobalt (Co) is an essential micronutrient for humans [30], [31] and its primary function is based on its role in cobalamin (cyanocobalamin=vitamin B₁₂). It is the only known metal-containing vitamin, in fact, the only vitamin for humans that is synthesized solely by microorganisms [31], [32]. In alkylcorrinoid cofactors the unique properties of the cobalt–carbon bond [32] are exploited to catalyze chemically challenging biotransformations [33]. As a cofactor for methylmalonyl-coenzyme A mutase and methionine synthase [34], cobalamin is active in both enzymes, which are important for human health [30]. Especially the dysfunction of methionine synthase causes disruption of many cellular processes and leads to disease [30]. Cobalamins occur “in legion” [32], [34], [35], yet in prokaryotes also rare non-corrin cobalt-dependent enzymes exist; the two more important ones are nitrile hydratase and methionine aminopeptidase [33]. Also recently it was discovered [36] that natural B₁₂-binding nucleotides function as “riboswitches”, relevant in controlling gene expression, and this opened a new research area in the B₁₂ field [37]. A similar step into the future is the replacement of cobalt by rhodium [38] in the coenzyme B₁₂ leading to a B₁₂ antimetabolite or antivitamin [38], [39].

Copper (Cu) was used by humans very early in history because it is found as metal on the Earth’s surface [40]. If oxidized it is a redox-active metal ion mainly in the form of the couple Cu^+/2+, similar to Fe^2+/3+; in its free, non-complexed form it needs to be tightly controlled to prevent harming cells due to its potential to catalyze the generation of toxic reactive oxygen species (ROS) [41]. Therefore Cu chaperones [42], [43] and consequently, homeostasis are important in eukaryotic [41], [44] as well as in prokaryotic cells [45]. Nutritional copper deficiency gives rise to anemia, neuropathies, impaired immune responses, etc. [41]. Genetic copper deficiency leads, e.g. to Menkes disease (MD) and distal hereditary peripheral neuropathy, whereas genetic copper overload gives rise, e.g. to Wilson’s disease (WD) and infantile cirrhosis [41]. Impairment of copper homeostasis can lead to neurodegeneration, as exemplified by MD and WD, and it has also been associated, e.g. with Parkinson’s disease [41], Huntington’s disease [41], and also Alzheimer’s disease [41], [46]. Finally, it needs to be noted that there is a huge number of Cu-containing proteins and enzymes [45], [47], [48].

Zinc (Zn) was recognized as an essential trace element for eukaryotes already in 1869 [49], [50]. In fact, next to iron, zinc is the second most abundant trace element in humans [50] with about 3000 zinc proteins [50]. Overall there are over 6000 enzymes [51] where zinc has either a catalytic or a structural function [49], [50]. Among the best known Zn enzymes are Cu/Zn superoxide dismutase [48], [52], carbonic anhydrase [51], carboxypeptidase [50], alcohol dehydrogenases [51], alkaline phosphatases [51], [53], and many more [51]. Of special interest are the zinc finger proteins in which Zn is bound tetrahedrally by a combination of cysteine (C) and histidine (H) ligands, the most common motifs being C2H2, C2HC or C4 [49], [50]. Zinc finger domains may act as DNA-binding units but may also mediate protein–protein interactions [49]. Zinc is also bound to metallothioneins, which play an important role in Zn uptake, distribution, storage, and release in cells [4], [50], [54]. Commonly, metallothioneins have a high cysteine content, but are low in aromatic amino acid residues. The Cys-X-Cys tripeptide sequence is characteristic, leading to metal thiolate clusters [54]. In the case of metallothioneins the storage of the metal ion is of relevance, whereas in the case of insulin Zn binding allows storage of the protein in an inactive form; the active form of insulin which is released into the bloodstream does not contain zinc [54].

Molybdenum (Mo) is, as far as its abundance on Earth is concerned, only at position 54 [55]. Yet, this 4d element is another metal in the PTE (Fig. 1) that is required as a trace element by all forms of life [56]. It also plays a crucial role in human health and disease [57], though it is present in our body only in a few-milligram quantity [55]. The oxyanion molybdate, Mo^VIO₄²⁻, is the only form that cells can take up from the environment [57], but Nature has developed two very different cofactors: One is the pterin-based iron-molybdenum cofactor (FeMoco) that is unique to a single enzyme, the bacterial nitrogenase which transforms N₂ to NH₃ [56], [58]. As far as the other cofactor Moco is concerned, two families exist: The sulfide oxidase family with a cysteine ligation, and the xanthine oxidase one with a terminal sulfido ligand [57]. The eukaryotic Mo enzymes are involved in key processes, that is, in the global carbon, nitrogen, and sulfur cycles, such as nitrate reduction, sulfite detoxification, and purine catabolism [57]; however, it is also of relevance for many products in industry [55].

2.3 d-Block metals that are essential for some forms of life

A further group of metals that are essential for some forms of life comprises vanadium, nickel, cadmium, and tungsten. We begin with the last mentioned metal because tungsten is closely related to molybdenum, which was just discussed above.

Tungsten (W) has atomic and ionic radii which are very similar to those of molybdenum [56], [58]; both trace metals are of relevance for prokaryotes [58]. However, in deep-sea hydrothermal vents W is favored because it exists as WO₄²⁻ or WS₄²⁻, whereas MoO₄²⁻ transforms to insoluble MoS₂. Therefore it is not surprising to find W-dependent hyperthermophilic bacteria (archaea) under these conditions [58]. Due to the chemical similarity under ambient conditions [56], [58], W can substitute for Mo in several enzymes [58], e.g. it can sustain the growth of Methanobacterium thermoautotrophicum [56], but some prokaryotic enzymes like those of the aldehyde oxidoreductase family are specific for W [58].

We shortly address now the other metals (V, Ni, Cd) that are essential only for some specific organisms:

Vanadium (V) is the 21st most abundant element in the Earth’s crust [59] and it is commonly taken up in food. The body pool of an average human being (70 kg body mass) amounts to about 1 mg [59]. Vanadium has a long and multifaceted history in medicine with numerous claims of its beneficial effects on human health [60], [61], but it has not been proven that it is essential for humans [59]. Its essentiality for some forms of life was first established in 1982/83 by the discovery of vanadium-dependent bromoperoxidase in the marine alga Ascophyllum nodosum [59]. The haloperoxidase enzymes that catalyze the oxidation of chloride, bromide, and iodide by hydrogen peroxide are well studied [62]. The other vanadium-based enzymes are vanadium nitrogenases [59], [62]. The one from Azotobacter vinelandii reduces not only N₂ to NH₃, but also CO to hydrocarbons as was recently reported [63]. Interestingly, this protein contains an additional α-helical subunit that is not present in molybdenum nitrogenase [63]. There are more vanadium-containing compounds present in Nature, like amavadin, an intriguing V(IV) complex that occurs (at least) in the toxic fungus Amanita muscaria [64], [65]. A catalase- and peroxidase-type activity has been demonstrated for amavadin, but its biological role has not yet been established [64]. Further examples for vanadium occurrence are found in ascidian families; the highest concentration of 0.35 m, which is 10⁷ times that of sea water, was observed in the vanadocytes, a type of blood cells, of Ascidia gemmata [66], [67]. Why ascidians accumulate vanadium to such high levels is not known. Notably, vanadium is not involved in O₂ transport as was once thought [66]. The antarctic fan worm Perkinsiana littoralis hyperaccumulates vanadium in its bronchial tissues; it is hypothesized that this is a natural chemical defence against predation [68].

Nickel (Ni) is widely distributed in the Earth’s crust; it ranks number 24 in the order of abundance of the elements [69]. However, no nickel-containing enzyme or cofactor is known in higher animals [70], but they occur in plants, bacteria, archaea, and unicellular eukaryotes. In this context Helicobacter pylori, a gram-negative bacterium, may be addressed [70], [71]. This pathogen colonizes the human gut, giving rise to acute and chronic gastric pathologies, including peptic ulcer, and possibly also to gastric carcinomas and lymphomas [70]. Indeed, the toxic effects of nickel and its compounds are well known [69], [70], [72]. Zerner and coworkers [73] established the biological role of nickel in enzymatic catalysis in 1975 when they reported the presence of Ni²⁺ in the urease produced by H. pylori. This discovery triggered efforts to understand the chemistry of nickel in other bio-systems. Subsequently, its presence was detected in CO dehydrogenase from photosynthetic bacteria, in methyl-coenzyme M reductase-bound factor Ni-F₄₃₀ from methanogenic bacteria, in bacterial [Ni-Fe]-hydrogenase from several microorganisms, in acetyl-CoA synthase from methanogenic and acetogenic bacteria, and in superoxide dismutase from actinomycetes [71].

Cadmium (Cd) occurs almost exclusively together with zinc minerals and hence, despite its low abundance, it is present ubiquitously in Nature [4], [74]. Cadmium is an element with considerable toxicity for humans [75], [76], [77] and it may be taken up in rather high, yet not phytotoxic, concentrations via the edible parts of plants [74]. Cadmium accumulates with age in metallothioneins [6], which are also involved in zinc and copper metabolism [75], [78]. Of biological relevance is its high affinity for sulfur sites, which means, e.g. that in metallothioneins with ZnS₄ units, Cd²⁺ concentrations need to be only one thousandth of those of Zn²⁺ for an effective competition [75]. Rather than acute lethal exposure, the chronic low cadmium exposure (CLCE), mainly from dietary sources, is the real challenge [76]. Because Cd²⁺ has a very long biological half-life, in the order of 20–30 years, Cd²⁺ exposure during childhood may affect health in old age. CLCE leads increasingly to organ toxicity, especially to nephrotoxicity [76]. Moreover, cadmium is a well-known human carcinogen [77]. Despite the indicated toxicity of Cd for many organisms, it is also essential for certain diatoms [79], though at high Cd concentrations it is toxic for these as well; in other words, Cd can either be beneficial or detrimental to phytoplankton, depending on the conditions. At relatively low concentration Cd can enhance the growth of several phytoplankton species under Zn limitation [79]. The only known natural protein containing Cd²⁺ [80] is a carbonic anhydrase with Cd²⁺ at its active center. The conformation of the cadmium-carbonic anhydrase active site is similar to the one containing Zn, and indeed, the two metal cofactors can be exchanged for each other [79].

2.4 Chromium, a special case

Chromium (Cr) in its hexavalent state, Cr(VI) (chromate), is genotoxic and a carcinogen for humans [6], [72], [81]. Now the question arises whether the other common and rather stable oxidation state of chromium, Cr(III), is essential. About 40 years ago chromium was classified as an essential trace element for animals and humans [82], but this view began to be challenged around the turn of the millennium [81] and is now questioned seriously [6], [83].

At present chromium cannot be classified as essential because “(i) nutritional data demonstrating chromium deficiency and improvement in symptoms upon chromium supplementation are lacking, and (ii) no biomolecules have convincingly been demonstrated to bind chromium and to have an essential function in the body” [83]. For the benefit of human health it is necessary to obtain a balanced and informed view based on solid (robust) and carefully deviced experiments [6]; one needs to determine (i) the specific biological molecules that are involved in the metabolism of Cr(III), (ii) the activity of biological Cr(III) complexes at specific sites of action, and (iii) the amount of supplemental Cr(III) that potentially causes long-term toxicity [6].

2.5 Selenium and further metalloids from the p-block

Selenium (Se), a half-metal or metalloid, is essential for all forms of life [84]; it is easily taken up via Se-rich food like oranges, tea, rice, mushrooms, etc. [85]. Selenium is situated in the p-block of the PTE (Fig. 1) and it has certain chemical aspects in common with sulfur, located in the same group. This relationship is evident from a comparison of the two amino acids cysteine and selenocysteine. The presence of an excess of selenium is associated with selenosis, while selenium deficiency gives rise to heart failure, skeletal muscle dysfunction, coronary artery disease, and other shortcomings [86]. Selenium exerts its biological functions through selenoproteins [84], [86]; e.g. four forms of Se-glutathione peroxidase were shown to be important in antioxidant defence [87]. More than 30 selenoproteins are known [86] and 25 Se-proteins are encoded in the human genome [84]. In selenoproteins Se is present mostly as selenocysteine, but selenomethionine occurs as well [84], [86]. It is clear that selenium plays rather diverse and important biological roles [56], [84], [86], [87].

There are two more metalloids of considerable biological interest in the p-block of the PTE, namely Silicon (Si) and Arsenic (As). However, both elements have not been proven as being essential for humans [88], [89], though for certain marine organisms, not discussed here, arsenic is essential [90], [91], [92], [93] and silicon is a key element in biomineralization of both marine fauna [94], [95] and of many plants [95]. Silica, in the form of asbestos (SiO₂) is a health hazard (asbestosis) that impairs lung function and increases cancer risk [88]. Nonetheless, silica has been reported to have potential beneficial effects on human health [88]. Well known is also the toxicity of arsenic oxide, which is deadly at high concentrations [89]; furthermore, it causes cancer of the skin, lung, bladder, liver, and kidney [89]. However, at low doses arsenic oxide is an approved and effective chemotherapeutic drug including for the treatment of promyelocytic leukemia [89]. Interestingly, recent advances in understanding the metabolism of arsenic in plants have led to seek a biotechnological intervention to reduce grain-arsenic in rice [96].

2.6 Some general comments about the metals of the p-block including lead

Next to metalloids or half-metals the p-block of the PTE contains the non-metals, which mostly provide the anions for living systems (S²⁻, SO₄²⁻, PO₄³⁻, Cl⁻, etc.). However, we concentrate here on the metals. Quite generally, many non-essential metal ions are present in human tissues, some at even higher concentrations than the essential ones, causing either beneficial or adverse effects because non-essential does not mean non-functional [6]. A possible deficiency, natural or experimentally induced, is characteristic for many essential metal ions [6]. Though some have pharmacological responses above their physiological concentrations, excess of a metal ion usually leads to toxicity [72], as was already known to Paracelsus who quoted that “all things are poison, and nothing is without poison, the dosage alone makes it so that a thing is not a poison” [97].

All metals (ions) of the PTE, including those of the p-block, are used in industry. One of the most widely used examples among the light p-block metals is Aluminum (Al). It is considered non-essential and even-nonfunctional for most forms of life, but for humans it has long been assumed that it may be a factor in the development of Alzheimer’s disease. However, research has not reached a stage where this action has really been confirmed [98], [99]. Indeed, occupational aluminum exposure was not associated with Alzheimer’s disease [100], but from renal dialysis in the early 1970s it is known that the use of water containing Al(III) leads to encephalopathy, a devastating brain disease [101], [102], [103]. Very recently it was asked [104]: Can the interaction of Al(III) with catecholamine-based neurotransmitters be a potential risk factor for neurodegenerative diseases?

A prominent case taken from the group of the heavy p-block metals, which we discuss more in detail, is Lead (Pb) [105], which is used in batteries, paint pigments, plumbing, etc. It has been known to mankind for thousands of years [106]. There is a figure made of lead in the British Museum which by now is nearly 6000 years old [107]. Lead was mined in Spain as early as 2000 B.C. and its toxicity was recorded already by Greek and Arab scholars [107]. The essentiality of lead has been discussed but not demonstrated [107], [108]. In fact, lead (for an overview see [105]) is not essential for life processes, instead it proves acutely toxic to most organisms [109]. It interferes with the metabolism of essential metal ions, particularly that of Ca, Fe, Cu, and Zn [110], [111]. Pb²⁺ can be a substitute for Ca²⁺ accumulating in bone [110]; indeed, the skeleton contains approximately 95% of the body burden of lead incorporated into hydroxyapatite with very high stability [110], the half-life being about 30 years. Lead produces adverse effects in mammals by acting on the nervous system giving rise to neurotoxicological effects, inducing inflammatory responses, modulating the immune functions, leading to anemia, affecting the cardiovascular system, genetic and reproductive machinery, etc. [110], [111]. The US Environmental Protection Agency (EPA) concludes that there is no safe exposure limit [110].

Lead(II) can mimic calcium(II) and also copper(II) because of its ambivalent coordination sphere resulting from the 6s² lone pair, which can be holodirected (symmetrical) or hemidirected (distorted/asymmetrical) giving rise to high or low coordination numbers, respectively [112], [113]. Therefore, the coordination chemistry of lead(II) is complicated with its varying coordination numbers ranging from 4 to 10 [114]. In fact, the hard-soft rule fails for this divalent metal ion. For example, the affinities of Pb²⁺ towards S donor sites are difficult to generalize: On the one hand Pb²⁺ forms rather stable complexes with nucleoside 5′-O-thiomonophosphates, Pb²⁺ being sulfur-bound. On the other hand, in a dinucleotide with a phosphodiester linkage, if one of the terminal oxygen atoms in the linkage is replaced by a sulfur atom, 10-membered macrochelate formation of the initially phosphate-bound Pb²⁺ occurs now with the O and not with the S site of the linkage [114]. Lead(II) is a hydrolytic metal ion with excellence in catalyzing phosphodiester cleavages [115] as is reflected by the leadzyme, which is a small ribozyme (catalytic RNA) that catalyzes the specific cleavage of a phosphodiester bond to yield a 2′,3′-cyclic phosphate, which undergoes then further hydrolysis to yield a 3′-phosphomonoester. Unlike in other small self-cleaving ribozymes, other divalent metal ions cannot replace Pb²⁺ in the leadzyme [115]. Interestingly, lead(II)-dependent DNAzymes (also called DNA enzymes, catalytic DNA or deoxyribozymes) have also been discovered and applied as biosensors for the detection of Pb²⁺ in the lower nanomolar range, not only in the test tube, but also in body fluids [115]. Furthermore, by the formation of a coordination polymer in water a selective and sensitive turn-on phosphorescent sensor for Pb²⁺ is created [116].

Notably, the toxicity of Thallium (Tl), the neighboring element of Pb in the PTE, is closely related to the action of lead owing to the same electronic characteristics of Tl(I) and Pb(II) (6s²) [117] giving rise also to flexible coordination numbers and geometries as well as variable affinities for hard and soft donors. Oral ingestion is the primary cause for toxicity. Because the ionic radii of Tl⁺ and K⁺ are similar, Tl⁺ can substitute for K⁺, e.g. in pyruvate kinase or in various Na⁺,K⁺-ATPases [117]. Most thallium salts are easily absorbed in the gastrointestinal tract. Thallium poisoning affects the central nervous system (CNS), it leads to tremor, psychosis, etc. [117].

2.7 Metal compounds used in medicine

Several metals of the PTE, that is, their ions and complexes, are employed in medicine. Some examples are summarized below; they are listed (essentially) according to their atomic number, beginning with lithium:

Lithium (Li) is of immense benefit to a large number of patients who suffer affective disorders [118], [119]. Mostly lithium carbonate, Li₂CO₃, in tablet form [119], is employed by the oral route [118], but some other lithium salts are occasionally also used. The chemistry of Li⁺ is closer to that of Mg²⁺ than to that of Na⁺ [118], [119]. The benefits and risks associated with lithium salt treatment in affective disorders have been summarized and evaluated [120].

Gallium (Ga) nitrate, (Ga(NO₃)₃ (for Ga chemistry see [121]), was recognized more than 30 years ago as an antineoplastic agent and this was confirmed in clinical trials (Phase 1 and 2) [121] in patients with lymphoma and bladder cancer [122]. Beyond the first generation of Ga(III) salts (parenterally administered) a new generation of complexes [e.g. tris(8-quinolinato)Ga(III)] with oral bioavailability has emerged and is now evaluated in the clinic [122]. Ga(III) shares chemical characteristics with Fe(III) and these enable it to interact with iron-binding proteins and to disrupt iron-dependent tumor cell growth [86], [122]. The discovery that radiogallium (⁶⁷Ga) localizes in tumors had led to the use of ⁶⁷Ga as a tumor-imaging agent in patients for several decades [86], [122], although more recently ⁶⁷Ga scanning is partly replaced by other imaging methods [122].

Strontium (Sr) can replace Ca²⁺ in many biological processes [123] and it is deposited in bone [123]. Indeed, Sr²⁺ salts are used for the treatment of osteoporosis because Sr²⁺ interferes, as a partial substitute for calcium, with the biomineralization and biodegradation processes of bones in humans. Strontium ranelate is currently the compound of choice [124]. It should also be recalled that ⁹⁰Sr is an important product of nuclear fallout [123]. It was investigated because of its deleterious effects in humans and animals [123].

Technetium (Tc)-based diagnostic metalloradiopharmaceuticals are widely used [86] (for ^99mTc history and chemistry see also [125], [126]). The synergy between theory and experiment has deepened the radiopharmaceutical application of ^99mTc [127], which is now the most commonly employed radionuclide in diagnostic medicine [127], [128]. Pertechnetate, TcO₄⁻, is the most stable form of Tc in aqueous solution [127]. For radiopharmaceutical purposes [125], ^99mTc being at the center of single photon emission tomography (PET) [129], ^99mTc (half-life ca 6 h [129]) must be converted into complexes which requires the reduction of pertechnetate into lower oxidation states [127]. The choice of the reducing agent and the specific reduction conditions are crucial because for medical applications kit formulations need to be provided [127]. The ^99mTc complexes have to be prepared in one step, in 30 minutes, and under aqueous conditions from generator-eluted ^99mTcO₄⁻ [129]. In the resulting compounds the oxidation states of Tc range from –I to +VII [126], [127]. The most extensively studied Tc(V) core is the [Tc=O]³⁺ moiety which can be used to obtain in vivo stable ^99mTc complexes [127]. The facile preparation of the Tc(I) complex [^99mTc(OH₂)₃(CO)₃]⁺ from ^99mTcO₄⁻, offered new avenues [129] by combining the fac-[^99mTc(CO)₃]⁺ core with the cyclopentadienyl ligand to give the (η⁵-C₅H₅)Tc(CO)₃ complex. By using substituted cyclopentadienyl derivatives, C₅H₂R₁R₂R₃, chemical modifications and a fine-tuning of the highly inert and uncharged complexes becomes possible [129].

Silver (Ag) has been used as an antimicrobial for thousands of years [130]. Well known is the application of solid silver(I) nitrate, AgNO₃, in form of the so-called “Höllenstein”, to disinfect wounds. Indeed, dilute solutions of silver nitrate served long, and still do in some countries, as antimicrobial ointment to be instilled into the eyes of newborn babies [131]. Today quite a number of silver-containing medical products are available, e.g. as dressings in burn wounds, wound-care products, catheters, dental implants, etc. [131].

Platinum (Pt)-based anticancer drugs are among the most widely used of all chemotherapeutic cancer treatments. Since the serendipitous discovery of the anticancer activity of Cisplatin, cis-diamminodichloroplatinum(II), by Barnett Rosenberg about 50 years ago [132], progress has been made to reduce the side effects [133] (nephrotoxicity, peripheral neuropathy, nausea, etc.) by applying special treatment regimes and also by using new platinum(II) complexes like Oxaliplatin [133] and analogues in the next step [134]. To combat Cisplatin-resistant cancers, polynuclear platinum(II) complexes were developed [135]. A further approach to avoid resistance is the application of octahedral and kinetically inert Pt(IV) prodrugs [136], [137], [138]. They can be reduced in cancer cells to active square planar Pt(II) complexes, e.g. by intracellular reducing agents such as glutathione or by photoexcitation.

Gold (Au) and its complexes have been used as therapeutics since ancient times [139], [140]. In modern medicine gold drugs like auranofin [139], [140] are applied for the treatment of rheumatoid arthritis, though they also serve as antiparasitic, antibacterial, and antiviral agents. Recently gold(I) and gold(III) complexes are also studied as antitumor agents [139], [140], [141]. One may add that lately also some technical aspects of applied gold chemistry were shortly summarized [142], [143].

Gadolinium (Gd) complexes (mostly in the form of complexes with macrocyclic ligands) have been [144] and to some extent still are used in magnetic resonance imaging as contrast agents [86]. The risks associated with gadolinium(III) use have been summarized [145] and recent reports about the development of nephrogenic systemic fibrosis lead to controversy regarding the safety of gadolinium-based contrast agents (GBCAs) in patients with preexisting renal insufficiency [145], [146]. Furthermore, dechelation of Gd(III) can result in the accumulation of the highly toxic free Gd³⁺ in bone, skin, liver, and brain tissue [146]. In 2017 this has led to a recommendation by the European Medicines Agency which restricts the use of some commonly employed GBCAs [86].