Metal Ions, Ligands and Complexes in Medicinal Chemistry

Figure 1: Anti-cancer agents.

Ligands are neutral or anionic molecule that donate a pair of electrons to a vacant metal orbital [1-2]. Ligands can be monodentate, bidentate, tridentate. The number of atoms of a ligand that is coordinated to a metal ion is referred to as its dentary. The union of a ligand and a metal orbital (p, d or f) will result in the formation of a complex of varying colors (Figure 1). These complexes can be diamagnetic (align with the magnetic field) or can be paramagnetic (oppose the applied magnetic field). Ligands can be high spin i.e., having the maximum number of unpair electrons or can be low spin, having the maximum number of paired electrons. Complexes come in a variety of shapes. These include planar, trigonal planar, square planar, trigonal bipyramidal [1]. The shape of ligands and complexes has influenced their interactions with receptor cells and thus mechanism of action. Chelator design can affect kinetic properties, catalytic mechanisms and donor interactions [2]. The Periodic Table consists of over 103 elements which mean that complexes are too numerous to mention (Figure 2). The union of a metal ion and a ligand is called a complex or a chelate. Metal ions, ligands and complexes have played important roles in medicinal and Pharmaceutical chemistry [3-6]. This paper outlines the application of Ligands and Complexes in medicinal and Pharmaceutical chemistry (Table 1).

Figure 2:Structure of budotitane.

Table 1:Functions of metal ions in medicine and Pharmacy.

Metal ions

Metal cations are present in the biological systems as chelates or coordination complexes [7]. Metal ions have diverse roles in the human biological system. These include calcium role in enamel and toothpaste, iron in blood and muscle function, molybdenum in the metabolism of purine, zinc in insulin and various enzymatic functions, Also, chromium in the metabolism of glucose and magnesium in the transmission of nerve impulses [8].

Metal complexes

Figure 3: Structure of a heteronuclear Ru-Cu terpyridine complex for DNA binding (Ru) and DNA cleavage (Cu).

Metal complexes have been used in the treatment of neurodegenerative diseases. These include their use in the treatment of Alzheimer’s disease (Figure 3). Chelating agents such as clioquinol and elesclomol have been used in the treatment of Alzheimer’s disease. Cis-Platin have been used for the treatment of testicular and ovarian cancer since 1978. Cis-platin kills cancer cells via cross-linking with the DNA strand and inhibition of transcription phenomenon [9-11]. Despite its curative purposes, Cis-platin is not effective as a Universal anti-cancer agent. This has led to the synthesis of other platinum compounds as anticancer agents. These include carboplatin, oxaliplatin, lobaplatin, heptaplatin etc. [12-13].

Figure 4:Structure of an Au-clotrimazole antiparasitic combination agent.

Titanium (IV) complexes such as badotitane, which is a β-diketonato complexes of titanium and titanium dichloride have shown antitumor activity in human clinical trials with low toxicity levels. However, these complexes are not stable [14]. Metal complexes have been used as combination agents to form a single compound, capable of modulating multiple targets simultaneously. For example, the combination of a DNA targeting agent with a DNA cleaving agent is shown in Figure 3 below. The DNA-cleavage activity of the redox-active Cu-terpyridine unit was significantly increased when attached to the Ru metal intercalator [15]. The ligation of anti-parasitic agent such as clotrimazole and ketoconazole with transition metals such as Cu²⁺ and Au²⁺ improves their activity against Trypanosoma cruzi (Chagas disease). It’s the imidazole moiety of these drugs that coordinate to the transition metal ions (Figure 4).

Vanadium ions such as vanadyl (VO²⁺) or vandate (VO₄^3-) enhances the effects of insulin and have been studied as antidiabetic agents [15]. On a similar note, bifunctional vanadium complexes have been developed using bioactive ligands based on metformin, thiazolidinediones and curcumin. Figure 5 shows the structure of a vanadium-thiazolidinedione coordination agent for diabetes therapy. Lanthanide coordination complexes show considerable emissive optical properties, exhibiting sharp metalbased emission bands and long luminescence lifetimes. As such they have been used as Magnetic Resonance Imaging agents. Lanthanide emission bands are sharp and are characteristic for each metal. The most common Ln3+ ions for optical imaging purposes are Eu3+ and Tb3+, as these ions exhibit optimal emissive properties [16-18] Luminescent Ru2+ complexes have been extensively studied as DNA binding agents and as cell imaging probes [19-20].

Figure 5: Structure of a vanadium-thiazolidinedione combination agent for diabetes therapy.

Ligand design is of crucial importance in their use in preventing metal ion overload, either from ingestion or a breakdown in the uptake, transport, or storage of essential metal ions, significant toxicity [21-22]. Toxic metal poisoning and metal overload disorders such as Wilson’s disease (Cu) and Hemochromatosis (Fe) are treated with metal ion chelators such as penicillamine, EDTA and deferoxamine [23-24], Figure 6. Metal ion dysregulation has been implicated in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s Disease (AD), Creutzfeldt-Jakob disease and Amyotropic Lateral Sclerosis [25]. 2,3-Dimercaptopropanol known as British Anti-Lewsite (BAL) is used as an antidote to Lewisite (dichlorovinylase). The first use of BAL was associated with arsenic therapies against syphilis and industrial accidents with arsenic [26].

Figure 6:Metal ion chelators.

Lanthanide coordination complexes show considerable emissive optical properties, exhibiting sharp metal-based emission bands and long luminescence lifetimes. As such they have been used as Magnetic Resonance Imaging agents. Lanthanide emission bands are sharp and are characteristic for each metal. The most common Ln³⁺ ions for optical imaging purposes are Eu³⁺ and Tb³⁺, as these ions exhibit optimal emissive properties [16-18] Luminescent Ru²⁺ complexes have been extensively studied as DNA binding agents and as cell imaging probes [19-20]./

Ligand design is of crucial importance in their use in preventing metal ion overload, either from ingestion or a breakdown in the uptake, transport, or storage of essential metal ions, significant toxicity [21-22]. Toxic metal poisoning and metal overload disorders such as Wilson’s disease (Cu) and Hemochromatosis (Fe) are treated with metal ion chelators such as penicillamine, EDTA and desferrioxamine [23-24], Figure 6 Metal ion dysregulation has been implicated in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s Disease (AD), Creutzfeldt-Jakob disease and Amyotropic Lateral Sclerosis [25]. 2,3-Dimercaptopropanol known as British Anti-Lewsite (BAL) is used as an antidote to Lewisite (dichlorovinylase). The first use of BAL was associated with arsenic therapies against syphilis and industrial accidents with arsenic [26].

Metal complexes of iron, gold, ruthenium, cobalt, rhodium, copper, cobalt, zinc, osmium and palladium have shown effective anti-malarial activity. The zinc (II) complex of amodiaquine, Figure 7 exhibited anti-malarial activity towards Plasmodium berghei [27]. Ligands of o-vanillin-(4-methylthiosemicarbazone) with Ga (III), Fe (III) and (III) have been shown to be active against malaria [28]. Ferrocenyl carbohydrate, Figure 8 have shown potential as an anti-malarial compound [29-30]. Sodium nitroprusside, Figure 9 interacts with a drug via its sulfhydryl groups to deliver nitric oxide. The latter causes fast vasodilation and acute lowering of the blood pressure [31-32].

Figure 7:Structure of zinc (II) with amodiaquine ligand

Figure 8:Ferrocenyl carbohydrate conjugate.

Figure 9:Structure of sodium nitroprusside.

Many azo dyes and coordination compound of azo dye inhibit the growth of bacteria and fungi. The chelate ligand of 1[(5-mercapto- 1-H1,2,4-triazole-3-y1) diazenyl]-naphthalen2-ol with metals of Mn²⁺, Co²⁺, Ni²⁺ and Cu²⁺, Figure 10 have shown potency against the growth of E. coli, S. aureus, A. flavus and C. albicans29.

Figure 10:Structure of Mn (II), Co (II), Na(II) and Cu (II) complexes.

Complex [CuCl2(bipy)(L)], Figure 11 has shown anti-fungal activity against Candida albicans and thus exhibited fungicidal activity against planktonic and sessile cells.

Figure 11:Coordination compound of Cu (II).

Metal ions, ligands and metal complexes play important roles in medicine and pharmacy. These include antimicrobial, antidiabetic, anticancer etc. activities. It’s important that ligands are properly designed to chelate metal ions to form complexes and of the best fit to interact with receptor cells. The same also goes for metal complexes or chelates. Ligands are effective in preventing metal ion overload. These include penicillamine, EDTA and desferrioxamine. Metal complexes activity can be augmented via a combination of other metal complexes bearing different hetero nuclear centers. Medicinal ligands can further increase their activity via coordination to selective metal centers.

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