Overview of Medicinal Inorganic Chemistry

Medicinal inorganic chemistry is an area of medicine that is still new. We are continually learning about the many ways inorganic chemistry can be applied to medicine and advancing the techniques we currently use. However, medicinal inorganic chemistry has been practiced for longer than we know. As we look into some examples from the past, we see the Egyptians used copper to sterilize their water back in 3000 BC. Around 1500 BC is when Egypt started incorporating various iron remedies. China and Arabia believed that gold must provide health benefits since it was such a valuable metal. Lastly, during the Renaissance era in Europe was when the nutritional value of iron was discovered (Orvig, 1999). These are just a few examples of the uses of inorganic chemistry for medicinal purposes. As you can see from those examples, metals play a big role in medicinal inorganic chemistry. This is because metals play an important role in many areas of our body.

Metals have an important characteristic that allows them to interact with the systems of our body effectively. Metals can easily lose electrons to form positively charged ions; therefore, making them electron deficient. Most biological molecules are electron rich. The attraction between the opposing charges allows for the interaction of positively charged metals with negatively charged biological molecules such as DNA and proteins. The cationic form of these metals is how metals are used in our body systems (Orvig, 1999). Some examples of metals being used for tasks in our body are the iron containing hemoglobin, zinc fingers, calcium containing bones, and metalloenzymes such as copper, zinc, iron, and manganese which aid in and speed up chemical reactions (Orvig, 1999). The use of these metals in our body leads to a question: Can we take advantage of the metals used within our system via inorganic chemistry to treat the human body? Trying to answer this question led to an area of medicine/chemistry that we call medicinal inorganic chemistry.

Diabetes mellitus is a metabolic disease characterized by a lack of insulin in the body. There are two types of diabetes. Type 1 diabetes is characterized by the inability of the pancreas to make insulin. The  cells of the Langerhans’ islets in the pancreas are not working properly. In Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), the pancreas produces insulin but the insulin cannot be used properly (Domingo, 2016). The development of diabetes in a person is serious because it can lead to many secondary complications such as atherosclerosis, cardiovascular disease, neuropathy, blindness, kidney failure, etc. (Sakurai, 2002). The importance of treating this disease is only rising as it was estimated in 2017 there are 451 million people with diabetes worldwide with that figure expecting to increase to 693 million by 2045 (Cho, 2018). We currently treat diabetes via daily injections of insulin or synthetic therapeutic substances. Although these methods show positive results, the continued administration of insulin via daily injections can be painful and elevate stress levels in patients while the synthetic substances can lead to side effects. Therefore, the development of new drugs is highly desirable (Domingo, 2016).

Vanadium was first discovered in 1813 by the mineralogist Del Rio. It was rediscovered in 1831 by the Swedish chemist Nils Gabriel Sefstom who named the compound vanadis, a nickname of the Germanic goddess of beauty. This name was given to vanadium because of the beautiful multicolored compounds that vanadium could represent depending on its oxidation state (Tsiani, 1997). In Figure 1 below, a representation of the many colors and their respective oxidation state are shown.

Figure 1. A representation of the colors and their respective oxidation states for vanadium.

Lavender represents an oxidation state of (+2), green represents an oxidation state of (+3), blue represents an oxidation state of (+4), and yellow represents an oxidation state of (+5). Vanadium can be found in skim milk, lobster, vegetable oils, grains, and cereals (Badmaev, 1999). Vanadium is a member of the biologically important transition elements. Transition elements can exist in different oxidation states and form complex ions which provides the ability to form coordination compounds. Vanadium is most commonly found in biological systems as the vanadate (+5) and vanadyl (+4) forms (Poucheret, 1998).

Vanadium is a metal with the potential of treating diabetes. This potential comes from vanadium’s structural and chemical similarity to phosphate. Vanadium, in the form of vanadate (~90% H₂VO₄^– + 10% HVO₄^2- at pH 7), is very similar to phosphate (H₂PO₄^–/HPO₄^2- at pH 7) (Rehder, 2012). Vanadate may form esteric linkages in an analogous manner to phosphate (Tsiani, 1997). Therefore, vanadate is more than likely involved in the regulation of phosphate-dependent processes (Rehder, 2012). In Figure 2 below, a representation of this similarity is shown.

Figure 2. A representation of the structural similarity between vanadate and phosphate.

Vanadium may also enhance activity of a component of the insulin receptor by inhibitory action on phosphotyrosine phosphatase (PTP). This would lead to an increase in phosphotyrosine content of the insulin receptor and in turn lead to its activation. A study stated that 3-day administration of vanadate to STZ, streptozotocin,- diabetic rats results in inhibition of a fraction of the PTP which has been associated with blood glucose level normalization (Badmaev, 1999). This antibiotic can disrupt the insulin producing cells in rats and provide a research model that represents diabetic rats. Thompson (2006) states that the irreversible inhibition of insulin receptor protein tyrosine phosphatases (PTPases) dominates all other biochemical effects in the case of peroxovanadates. For vanadyl complexes, vanadyl may stimulate cystolic protein kinases and bypass the insulin receptor altogether (Thompson, 2006). Overall, the mechanism behind vanadium’s anti-diabetic effects are is definitely linked to its similarity with phosphate. However, the specific mechanisms behind each specific vanadium derivative or compound are a little more unclear.

Vanadium compounds that show insulin effects are called insulin mimetics. Both biologically active forms of vanadium, vanadyl and vanadate, have been demonstrated to possess insulin-like effects (Badmaev, 1999). A review article by Domingo (2016) studying the literature of the past thirty years on vanadium and its insulin mimetic effects provides evidence of vanadium as a viable anti-diabetic compound. Domingo states that vanadium and its insulin mimetic effects were first popularized by a study by Heyliger (1985). This study reported that vanadium, in the form of sodium orthovanadate, reduced the blood-glucose levels as well as prevented depressed cardiac performance that is associated with diabetes in STZ-induced diabetic rats. This study led to a number of investigators conducting studies on vanadium’s potential role in treating diabetes. These new studies along with their positive results in the early 1990s led to the interest of assessing vanadium therapy in human diabetes (Domingo, 2016).

Domingo’s article looks at two studies that studied the effects of vanadium on diabetes in human patients. Cohen (1995) studied the effects of vanadyl sulfate on six non-insulin-dependent diabetes mellitus (NIDDM) patients. He found that vanadyl sulfate improved both hepatic and peripheral insulin sensitivity. Goldfine (1995) studied the effects of oral sodium metavanadate on 5 insulin-dependent diabetes mellitus (IDDM) patients and 5 NIDDM patients. He found that oral sodium metavanadate increased basal mitogen-activated protein and S6 kinase activities in both types of diabetic patients. These results mimicked the effect of insulin stimulation in controls. The insulin-mimetic potential and anti-diabetic effects of vanadium have been clearly demonstrated through research in both diabetic rats and diabetic humans (Domingo, 2016). Another review article stated that studies found vanadate to stimulate glucose uptake, glucose transport, oxidation, decreased lipolysis, and many other improvements (Badmaev, 1999).

Although the review articles by Domingo (2016) and Badmaev (1999) have shown previous literature providing strong evidence that vanadium leads to positive results and improvements in diabetic individuals, the side effects of vanadium are not promising. Referring back to the Cohen (1995) study, he found that five out of six of his patients experience mild GI symptoms including diarrhea, nausea, and abdominal cramps. Referring back to the Goldfine (1995) study, he found that his patients experienced GI intolerance with vomiting in one patient and diarrhea in four patients. Domingo (2016) states that vanadium toxic effects in healthy and STZ-induced rats include hematological and biochemical alterations, reproductive and developmental toxicity, renal toxicity, carcinogenicity, and mutagenicity (Domingo, 2016). In contradiction to these adverse side effects found in the above studies, a study by Soveid (2013) assessed the long-term efficacy and safety of oral vanadyl sulfate in fourteen type 1 diabetic patients. Not many studies in type 1 diabetic patients had been conducted up to this point in time. He found that the insulin requirement of the patients was reduced 30% and the mean fasting blood sugar decreased. This study did not find significant side effects throughout the 30 months of treatment. This study concluded that vanadium was effective and safe for type 1 diabetic patients. Domingo states that he finds these results to be surprising in light of the previous research concluding there are toxic side effects.

The positive anti-diabetic results from these studies along with their toxic side effects led to a question for scientists. Can potency be improved to minimize the adverse effects while keeping the positive results? This is when bis(maltolato)oxovanadium(IV), BMOV, was created. A study showed that BMOV was two to three times more effective acutely than vanadyl sulfate as a glucose lowering agent, better tolerated than inorganic vanadium salts, and resulted in reliable glucose-lowering in animal models (Thompson, 2006). The potency of BMOV is about 50% greater than that of vanadyl sulfate (Barrio, 2010). BMOV normalized heart function in STZ-diabetic rats and 60% of untreated STZ-diabetic animals developed cataracts comparted to 8% in BMOV-treated animals (Badmaev, 1999). These studies show that vanadium in the form of organic complexes appear to be superior to the inorganic vanadate or vanadyl. This led to BMOV being submitted to clinical trials in the form of BEOV, its ethylmaltol analogue. In Figure 3 below, a representation of BMOV and BEOV is shown.

Figure 3. A visual representation of BMOV and its ethylmaltol analogue, BEOV.

BEOV advanced to phase II in clinical trials but drug development came to a stop due to renal problems observed in some patients (Scior, 2016).

 In conclusion, metals have been used in daily life for many years dating back to the Egyptians in 3000 BC. Since the discovery of how metals interact with our bodies, scientists have tried to take advantage of metals via inorganic chemistry to help treat the body. One example of that is in the possible treatment of diabetes. The current use of insulin to treat diabetes is slow and can lead to adverse effects over a period of time (Sakurai, 2002). Other viable treatment options are of interest to scientists because of this. Vanadium is one of the treatment options that has been studied. The mechanism behind its anti-diabetic effects is contributed to its similarity with phosphate.  Phosphate plays a major role in the many processes of our body and the similarity of vanadium to phosphate allows vanadium to interact with the processes phosphate is involved with. Vanadium and previous studies regarding its anti-diabetic potential have shown improvements in both diabetic animals and humans. Although improvements and positive results have been shown, these studies also report a level of toxicity causing GI tract health issues such as vomiting and diarrhea, while other studies have also reported adverse effects such as carcinogenicity and reproductive toxicity (Domingo, 2016). Therefore, vanadium compounds in the form of organic complexes, such as BMOV, have been formed to try and decrease the does needed/increase the potency of the vanadium compounds. These new compounds seek to accomplish the same therapeutic effects with a lower does which in turn would decrease its toxicity and possibly alleviate the GI problems associated with vanadium compounds (Badmaev, 1999). Studies have shown that BMOV and its derivatives accomplished the job of decreasing overall toxicity and side effects while maintaining the anti-diabetic potential. However, when BMOV and its derivatives were submitted to clinical trials, testing ceased due to renal toxicity found in patients. Overall, vanadium has continually shown its potential for treating diabetes; however, its persistent toxicity and resulting side effects from treatment have not made vanadium a viable treatment option for diabetes up to this point. Most of the studies were over short periods of time and toxicity has still presented itself. Scior (2016) states in his study that long-term toxicity and tissue accumulation issues are of major concern as diabetes requires a life-long drug administration against the chronic disease. Domingo (2016) goes on to state that he has concluded that there is no sense in 2016 to still insist on the possible use of vanadium compounds in diabetes therapy.

References

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(2)   Barrio, D. A.; Etcheverry, S. B. Potential use of vanadium compounds in therapeutics. Curr. Med. Chem. 2010, 17 (31), 3632–3642.

(3)   Cho, N. H.; Shaw, J. E.; Karuranga, S.; Huang, Y.; da Rocha Fernandes, J. D.; Ohlrogge, A. W.; Malanda, B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract, 2018, 138, 271-281.

(4)   Domingo, J. L.; Gómez, M. Vanadium compounds for the treatment of human diabetes mellitus: A scientific curiosity? A review of thirty years of research. Food Chem. Toxicol. 2016, 95, 137-141.

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(6)   Poucheret, P.; Verma, S.; Grynpas, M. D.; McNeill, J. H. Vanadium and diabetes. Mol Cell Biochem, 1998, 188(1-2), 73-80.

(7)   Rehder, D. The potentiality of vanadium in medicinal applications. Future Med. Chem. 2012, 4(14), 1823-1837.

(8)   Sakurai, H. A new concept: the use of vanadium complexes in the treatment of diabetes mellitus. Chem Rec, 2002, 2(4), 237-248.

(9)   Scior, T.; Antonio Guevara-Garcia, J.; Do, Q. T.; Bernard, P.; Laufer, S. Why antidiabetic vanadium complexes are not in the pipeline of “big pharma” drug research? A Critical Review. Curr Med Chem, 2016, 23(25), 2874-2891.

(10)           Thompson, K. H.; Orvig, C. Vanadium in diabetes: 100 years from Phase 0 to Phase I. J Inorg Biochem, 2006, 100(12), 1925-1935.

(11)           Tsiani, E.; Fantus, I. G. Vanadium compounds: biological actions and potential as pharmacological agents. Trends Endocrinol. Metab. 1997, 8(2), 51-58.