By: Zaelig Averch
The role of inorganic molecules in therapeutic medicine has evolved over the last century. Specifically, metal ion-containing drugs have been applied to a wide range of uses including anti-pathogenic and anti-cancer treatment. Although key to their versatility, the therapeutic use of these compounds is hampered by the toxicity of the metal ions they contain. This systematic review aims to describe the history of metallopharmaceutical chemistry, their advantages, disadvantages, and whether or not they may still serve a purpose when organic alternatives are available.
Medicinal inorganic chemistry deals with the application of inorganic compounds, especially transition metal complexes to therapeutic uses. It’s still an extremely young field in the discipline of medicinal chemistry, but it holds enormous promise. The introduction of metal ions into human biological systems has proved to be useful both diagnostically and therapeutically. For example, Magnetic Resonance Imaging (MRI), one of the most widely used diagnostic techniques, utilizes the lanthanide transition metal gadolinium (III) as a contrast agent.1 Therapeutically, there are a myriad of applications of metallodrugs, including in anti-cancer drugs, mood stabilizers, antidiabetics, antiarthritics, antimicrobials, antivirals, and antiparasitics.
The diverse applications of metallodrugs is due, in part, to the great variety and complexity of ligands that can be used within a single metal complex. Additionally, the expanded valence of transition metals allows coordination of up to twelve ligands, making metallodrugs extremely versatile tools in clinical settings. These treatments, however, are not without their drawbacks. The successful implementation of metallodrugs is made difficult by the toxicity of the metals used and their resultantly narrow therapeutic indexes.
‘Magic Bullet’ Treatments
Paul Ehrlich, a German-Jewish chemist, helped pioneer the field of therapeutic metallodrugs with his development of Salvarsan in 1912. It was proven to be an effective treatment against syphilis and has subsequently been recognized as the first modern antimicrobial agent.2 Prior to the development of Salvarsan, the primary treatment for syphilis utilized mercury, which is extremely toxic and has been demonstrated to cause cognitive decline after acute exposure.3 After its introduction in 1912, Salvarsan rapidly replaced mercury treatment, despite the fact that Salvarsan is an organoarsenic compound, making it also quite toxic, with a tendency to ‘burn up veins’.
Salvarsan offers a good historical example of the drawbacks of metallodrugs and the challenges that face their successful implementation. The medical application of metallodrugs is severely limited by the toxicity of many transition metals compared to organic compounds. This is why sixteen years later, in 1928, the organic antibiotic penicillin quickly replaced salvarsan for the treatment of syphilis and many other diseases. While metallodrugs are very attractive to pharmaceutical researchers because of their amazing versatility of structure and function, these treatments must be cautiously implemented because of their potential toxicity.
As a result of the toxicity risk, the most well-researched applications of metallodrugs are for the treatment of potentially terminal diseases, for which patients often don’t have any other recourse. Additionally, the cytotoxicity of metallopharmaceutical drugs can, in fact, be an advantage, especially in their application as antimicrobials and anti-cancer drugs. One of the most famous examples of a metal-containing anti-cancer agent is cisplatin (Platinol) which was discovered in 1965 by Barnett Rosenberg and Loretta VanCamp at Michigan State University. Since its discovery, cisplatin has been used for the treatment of bladder, head and neck, lung, ovarian, and testicular cancers. It’s widely effective against many types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas.4
The mechanism of action of cisplatin highlights the way toxicity can be used to a therapeutic advantage. Upon entering the cell, cisplatin hydrolyzes, losing two chloride ions (Figure 2) and becoming a potent electrophile with a 2+ oxidation state that is able to react with the nitrogen atoms in nucleic acids. Specifically, cisplatin is able to bind to the N7 reactive center of purine residue nucleotides like guanine and adenine. Since the oxidation state of hydrolyzed cisplatin is 2+, it is able to bind to two nucleotides, causing an irreversible blockage to DNA replication, triggering apoptotic cell death. This method of action may kill healthy cells in addition to cancerous ones, and has been correlated with many of the toxicological effects of cisplatin, including nephrotoxicity,5 hepatotoxicity, cardiotoxicity,6 and congestive heart failure.7 Despite these potential side-effects, cisplatin is a highly effective anti-cancer agent. This is because its method of action affects DNA replication, which occurs more frequently in rapidly dividing cancerous cells than in normally functioning somatic cells.
Cisplatin and salvarsan are good examples of metallodrugs created as ‘magic bullet’ treatments. Both are highly cytotoxic drugs intended to target a specific foreign attacker, either rogue cells that cause cancer or the bacterium treponema pallidum that causes syphilis. This ‘magic bullet’ type of treatment was relatively common with early metallodrugs, reflecting the difficulty of balancing the versatility of organometallic pharmaceuticals with their potential toxicity. This issue revolves around the difficulty of limiting the cytotoxic effects of these drugs only to target cells, which has the potential to result in a number of side effects potentially even more serious than those cited regarding cisplatin. For example, the antiparasitic arsenic-containing drug melarsoprol has been used since 1949 to treat trypanosomiasis (African sleeping sickness), despite the fact that it causes encephalopathy; damage or disease affecting the brain and cognition.8 This incredibly deleterious side-effect would completely eliminate the therapeutic use of melarsoprol if it wasn’t for the fact that untreated trypanosomiasis is nearly 100% fatal.9
BMOV, BEOV, and BBOV
The problem of toxicity is exacerbated in certain clinical applications that require high or repeated doses of medication many times a day. Type I diabetes is a good example of a serious autoimmune disease that requires frequent redosing of medication to maintain normal levels of insulin in the body throughout the day. In 1977, it was discovered that two vanadium salts, bis(maltolato)oxovanadium(IV) (BMOV) and bis(ethylmaltolato)oxovanadium(IV) (BEOV), were able to reverse most diabetic symptoms in diabetic lab rats. This promising initial finding was quickly tempered during pre-clinical trials. Vanadium is a potent toxin and can, in high enough blood concentrations, inhibit sperm motility, causing infertility in males.9, 10 Vanadium toxicity has also been linked to gastrointestinal and urinary disease, as well as fetus malformation. These side effects became distinctly problematic because the repeated doses necessary to maintain proper insulin release resulted in the accumulation of vanadium in the pancreatic tissues of lab rats. Importantly, successive research on vanadium-containing anti-diabetic drugs has yielded the synthesis of compounds like bis((5-Hydroxy-4-oxo-4H-pyran-2-yl)methylbenzoatato)- oxovanadium(IV) (BBOV) which was synthesized in 2013, and has half the oral toxicity, with the effective dose lowered by a factor of 1000.
The evolution of BBOV from BMOV and BEOV showcases an important part of the way these drugs are developed, similar to the way salvarsan replaced mercury treatments for syphilis. Typically the first generation of a metallodrug is fraught with toxicity issues, either eliminating their usefulness entirely, or limiting it as a last line of defense treatment. Successive generations, however, improve upon the structure to decrease the necessary dose to the point where the amount of heavy metal consumed per dose is less than the amount the human body can excrete in between doses.
Toxicity and the Therapeutic Index
The toxicity of metallodrugs is linked to the difficulty with which they are excreted.11 The metabolism of water-insoluble heavy metal complexes also depends on the presence of cellular antioxidants that are able to quench free radicals by suspending the activity of enzymes like catalase, peroxidase, and superoxide dismutase. Excretion for water-soluble complexes, on the other hand, is correlated with their ability to be successfully filtered from the blood via the kidneys. Many small metals like sodium pass easily through the nephron, but larger heavy metals are often unable to diffuse into the urine as easily, making nephrotoxicity a common side effect of overdose on many metallodrugs (Table 1).
This delicate balance between effective doses and excretion is well described by a drug’s ‘therapeutic index’ which is defined as the window between a drug’s therapeutic and toxic effects. As soon as a therapeutic index can be determined, that is, as soon as a specific dose is found to be consistently more therapeutic than toxic, the treatment can be widely implemented. In fact, the window between therapeutic and toxic effects doesn’t even need to be very wide for a drug to be approved for treatment. Take the example of lithium carbonate, an oral mood stabilizer that was FDA approved in 1970 to reduce suicide risk and mood swings in bipolar patients.12 Lithium’s exact method of action is yet unconfirmed. However, it has been proposed that it reduces cellular levels of myoinositol, high concentrations of which are found in the neurons of bipolar patients during manic and depressive episodes. Unfortunately, myoinositol is a necessary growth-promoting factor in mammalian cells, and a deficiency can result in intestinal lipodystrophy (AKA Whipple’s disease) which can be fatal if untreated.13 No matter the mechanism of toxicity, lithium has been widely demonstrated to be toxic in doses very near the therapeutic dose for bipolar patients. As a result, lithium carbonate has a very narrow therapeutic index.14 So narrow, in fact, that many bipolar patients prescribed lithium also undergo lithium decontamination during or after treatment.
Further illustrating the difficulty of a narrow therapeutic index, lithium carbonate has been examined as a potential treatment for neurodegenerative diseases like Alzheimer’s disease. Lithium ions exert a neuroprotective effect on the amygdala, hippocampus, and prefrontal-cortical regions of the brain.15 This treatment, while being potentially groundbreaking for patients suffering from Alzheimer’s or Parkinson’s disease, has been deemed unsafe due to the necessity of lifelong intake of lithium in moderate to high doses.
A major reason that so many metallodrugs have such narrow therapeutic indexes is a result of their complicated coordinated structures. The method of action of many of these drugs is poorly understood as a result of the complex steric and coulombic interactions between the charged metals and their often bulky ligands. As a result, many drugs in addition to lithium carbonate, like auranofin which contains a gold (I) center, have been heavily criticized despite their clinical efficacy.16 Auranofin in particular, like a number of other gold (I) compounds, has been shown to slow the progression of rheumatoid arthritis by inhibiting several cathepsin proteases implicated with the disease.17 The exact mechanism by which these cathepsins are inhibited is poorly understood however, leading practicing physicians to prescribe these gold medications as a last resort when other treatments have failed.
Despite the field of metallopharmaceuticals rapidly expanding over the last hundred years, it still remains less fully developed than traditional organic treatment routes. There are twelve metals essential to human physiology, and our bodies have developed a complex and sensitive system of pathways for their transport and utilization. This complexity poses a core challenge to the development of novel metallodrugs. The human body’s sensitivity to these metals is both a blessing and a curse for organometallic pharmaceutical researchers. While these drugs can be incredibly potent and their unique geometry makes fine-tuning their functionality a tantalizing possibility, their toxicity and often extremely narrow therapeutic indexes demand caution when developing any treatment involving the use of heavy metals.
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