Abstract
Organic chemistry is a very substantive area of study in chemistry. Therein, the physical and chemical properties of matter containing carbon are investigated. In addition to that, the various chemical processes that revolve around such compounds are further examined. The study of organic substances is quite relevant to appreciate their behavior, both, in their natural form and when incorporated into other substances. Among the several classes, compounds that fall under organic chemistry are carbenes. The essay interrogated carbenes with a particular bias to N-heterocyclic carbenes. Therein the author effectively prosecuted arguments that help explain the nature of the compound mentioned. To satisfy the reader, the author looked at the various physical and chemical properties of N-Heterocyclic carbenes. The intention was to develop the readerâs interest in understanding more about the compoundâs chemical reactions. It is at that juncture that the reader is allowed to appreciate the compoundâs possible use as an antitumor metallodrug.
Introduction
According to Clayden, Greeves, and Warren (2), carbenes used to be very reactive, and as such, little interest was accorded to their study. Clayden et al. (7) later retracted their initial opinions about the impossibility to isolate a stable compound of the chemical family in reference. That retraction was a result of the discovery of a stable form of carbene by Igau et al. (19). That carbene was referred to as a âpersistent carbeneâ.
The most common of these persistent carbenes are the diaminocarbenes. Such compounds have a general chemical formula in the form of (R2N)2C: In that formula, the Rs connote the functional groups present. The groups are very important to the process (Morisson et al. 13). Imidazole is an example of such a compound.
The essay will therefore examine the N-heterocyclic forms of carbenes. To this end, the author will attempt to satisfy certain attributes of these compounds. The author will examine their physical and chemical properties. The purpose is to develop the readerâs interest to appreciate the main argument of the paper. The main argument is the application of the N-Heterocyclic carbene in the development of possible antitumor metallodrugs.
The majority of drugs available in the market are either organic compounds or natural products (Wolfgang 113). However, their applicability has been waning and as a result of that, researchers have been exploring other options. Towards that end, researchers have been making huge strides towards the development of metallotherapautic drugs. It is important to appreciate that metallodrugs are the usual natural products used in the production of pharmaceutical drugs. The only difference is that their function ability has been improved by the incorporation of a metal element in the compound. Similarly, research has been ongoing towards the realization of metal-based diagnostic agents, which will further assist in the detection of diseases. Wolfgang (114) thinks that metal-based complexes provide alternative drug action mechanisms owing to their kinetic properties.
Properties of N-Heterocyclic Carbenes
To fully appreciate the application of N-heterocyclic carbenes, their properties must be examined. The paper will look at both physical and chemical properties as analyzed by Huynh (5389).
Physical Properties
By being a stable carbene, N-heterocyclic Carbenes exist as liquids. In addition to that, they possess no color. Therefore when placed in a transparent beaker it will be to describe N-Heterocyclic carbenes as colorless liquids. Huynh (18) further adds that the compound under investigation has extremely low melting points. In addition to all that, N-heterocyclic carbenes can sublime when exposed to low temperatures within a vacuum. For this study, the author finds that one particular property is of much relevance. Their resonance property is ideally the property that necessitates them to be coupled with metallic elements.
According to Huynh (5389), N-heterocyclic carbenes have a shift of their carbonic atom within the 13C-Nuclei Magnetic Resonance (NRM) spectrum. The NRM is the ability of the nucleus of an atom to absorb and subsequently emit radiation especially when placed within a magnetic field. It is that physical trait of resonance that strongly helps in the development of metal-based complexes.
Chemical Properties
According to Dyson and Jaouen (2445), N-Heterocyclic carbenes are strong bases. The property was documented after a chemical reaction was done using imidazole-2-ylidenes. From the results, it was also noted that the compound is reasonably nucleophilic. By being nucleophilic the N-Heterocyclic carbene can donate electrons to another compound that accepts such electrons during a chemical reaction. Their ability to donate electrons is also what makes N-heterocyclic carbenes able to be coupled with metallic compounds like platinum.
Another chemical property exhibited by the compound under review is dimerization. According to Metzler-Nolte (3), dimerization is the ability of a compound to be formed as a result of the combination of two identical molecules. As a result of this, Metzler (17) sought to clarify that carbenes and, by extension, N-Heterocyclic carbenes can dimerize reversibly. The dimerization is important in the stability of the compound. The explanation behind this is the electronic interaction that exists when lone pair of electrons is allowed to be nearby. The stability of the compound as a result of dimerization will also be proven to be important in the development of the metallodrugs.
Owing to their nucleophilic nature, N-Heterocyclic carbenes can take part in both addition and insertion reactions. Jaouen (15) points out that to subject N-heterocyclic carbenes to chemical reactions; care must be applied to ensure that at the point of reaction, they are truly stable. He opines that only stable compounds can yield successful byproducts from the two reactions mentioned herein.
Complexation is the ability of a compound to coordinate with an element to yield certain complex compounds. Hartinger and Dyson (391) point out that N-Heterocyclic carbenes just like the other carbenes can yield complex compounds when paired with other elements. Within the periodic table are several examples of elements that can be paired with the compound under review. Some of the elements include silver, gold, and platinum. The author mentions the three owing to their application in the development of metallotherapautic drugs. Therefore, it is important to appreciate that complexation, as a property, is the most relevant as far as the development of drugs with an improved metallotherapautic profile.
As far as the push to advance the pharmaceutical profile of metallodrugs is concerned, the author is quick to point out the existence of such kinds of drugs. Hartinger and Dyson (392) elaborately point out the existence of such antitumor metallodrugs in the name of cisplatin. The drug is produced as a result of the coupling of Platinum and the N-Heterocyclic carbene.
The platinum-based complex has had its positive impact on medicine however as the paper shall outline, cisplatin has had its limitations. It is through such limitations that Hartinger and Dyson (398) point out several research undertakings in the field of metallodrugs. As earlier indicated several metals can form complexes with N-Heterocyclic carbenes. However, the paper places more emphasis on Platinum, Gold, and Silver owing to the positive results in the test subject.
Metal N-Heterocyclic Carbene Complexes
As earlier stated the paper shall look at the application of N-heterocyclic complexes in the manufacture of drugs that can address such ailments as tumors. In that regard, the author relied on the Complexation property of carbenes. Such is what informed the development of metal N-heterocyclic complexes using silver, gold, and platinum (Jaouen and Dyson 2447).
Silver N-heterocyclic Complexes
According to Metzler (23), silver complexes have, for several years served as antimicrobial agents. He further adds that their usage has evolved into antiseptic purposes, which is presently the case. He also points out that silver complexes have been known to exhibit some antitumor tendencies, especially towards cancer-related tumors.
Navarro et al. (1070) point out that silver complexes exhibit similar modes of action. In their mode of action, silver complexes release their cations (Ag+). Upon their release, the Ag+ penetrates the cell membrane of the tumor and disrupts the normal functioning therein. The major setback with drugs containing silver is that their effect is temporal owing to the almost instantaneous release of the Ag+ from the cell. Navarro et al. (1073) therefore encourage the development of such drugs with coordinating ligands, strong enough to inhibit that fast release of the silver cations. By using Silver N-heterocyclic carbene complexes such a setback has been overcome.
Silver N-heterocyclic carbene complexes are developed by synthesizing imidazolium salts with Silver Oxide or Silver carbonate (Navaro et al. 1073). The resultant compound possesses a strong Ag-C bond. It is through such kind of stability that silver N-heterocyclic carbene complexes overcome the limitations of the other initial silver complex drugs.
Chang and Fujish (14) observed that all the silver-related complexes developed using N-heterocyclic carbenes were found to have positive medicinal results. As a result of that, it was found further possible to derive such complexes from 4,5-dichloro-1H-imidazole. The silver complexes derived thereof demonstrated cytotoxic activity against cells that cause breast and ovarian cancer.
Gold N-heterocyclic Carbene Complexes
The application of complexes of gold in medicine dates back many years ago (Metzler 37). Rodrigues points out some of their pharmaceutical purposes to include arthritis and cancer. There are is a wide array of gold complexes that can inhibit cell growth. The complexes vary depending on the ligands that are attached to the gold. The author used the works by Navarro et al. (38) to further establish the effect of the aforementioned variance. It was found that the use of varied ligands subsequently dictates the mode of action for the gold complexes on the cells.
The modes of action, of the gold complexes, ranging from DNA damage, alteration of the cell cycle as well as the inhibition of other cell processes among others. Such modes of action ultimately trigger what is called apoptosis, which Metzler (43) terms as programmed cell death. It is imperative to note that the cells in reference are the cancerous cells earlier stated. The author, therefore, finds that the pharmaceutical profile of respective gold complexes is, thus, highly dependent on the ligands attached to the gold.
The gold complexes that are used in treating tumors exist in two major structures (Thompson and Barta 35). The two structures are auranofin and Et3PAuCl. Thompson was able to determine their antitumor property owing to the ability of the complexes to inhibit the activity of the enzymes. Of particular interest is the enzyme TrxR found in cancerous cells.
The aforementioned enzyme is very essential in the normal functioning of cancerous cells. That gold complexes can inhibit their activity is a huge boost as far as the treatment of tumors is concerned. Thompson and Barta (35) also pointed out that the inhibition occurs as a result of the formation of a carbon bond between the complex and the enzyme at its Se-centre.
Platinum N-heterolytic Carbene Complexes
When it comes to the treatment of the different solid tumors, Youngs and Crintel (41) propose the use of platinum-based antitumor drugs. Such drugs have shown efficiency in the treatment of tumors like colorectal and genitourinary tumors. Towards that end, cisplatin has been used in chemotherapy regimens either singly or alongside other cytotoxic agents for over three decades. The antitumor activity of cisplatin is exhibited by the interference of the replicative and transcriptive ability of DNA in the cancerous cells. It forms adducts that are responsible for the interference. However, the efficiency of cisplatin is impeded the toxic side effects as well as tumor resistance.
To overcome the setbacks mentioned Youngs and Crintel (41) point out the experiments done on several platinum complexes. Since each experiment had goals unique to itself the aim was among others to reduce cisplatinâs toxicity which included nausea and vomiting. In addition, the researchers aimed to override the resistance to the drug as well as to increase the drugâs spectrum of activity.
It should also be appreciated that efforts have been made to comprehend cisplatinâs cytotoxic activity. The same has led to the synthesis of better antitumor agents that are platinum laced. Basing his arguments on the aforementioned, Metzler (117) analyses some of the emergent techniques of synthesis. They include such steps as making changes to the coordinated nitrogen ligand. Moreover, he further suggests the need to alter the type of the metal center. In addition, the scholar calls for the use of platinum complexes that are not highly reactive or toxic either and that they should easily dissolve in water.
In that respect, the author finds that Platinum N-heterocyclic complexes promise a revamped avenue for the development of better cytotoxic drugs. Skander and Marine (2146) were able to develop trans-configured square planar species by mixing N-heterocyclic carbene-amine Platinum complexes. The author notes an overall improvement in the efficiency of the complexes about cisplatin. For instance, it was observed that some of the complexes did well as compared to cisplatin in as far as lung cancer cells were concerned (Skander and Marine 2148).
Subsequent research (Adhikary et al. 763) further gave rise to complexes whose performance as antitumor drugs outshone cisplatin. The author relies on the experiments to authoritatively vouch for the use of platinum N-heterocyclic carbene complexes as superior antitumor drugs in comparison to cisplatin.
Conclusion
The paper, by having its domain in organic chemistry, has settled on carbenes as the chemical family to be reviewed. Therein the author has critically analyzed the possibility of having the said chemical family, contribute towards the development of antitumor metallodrugs. The reason behind this has been the setbacks that the current drugs have suffered towards realizing the same. The author relied on the N-heterocyclic carbenes to satisfy the reader with the subject matter of the paper. Towards that end, the author examined the various chemical properties of the said complexes.
The paper finds that cisplatin, as a drug, has been quite significant in the medical field as far as treatment of solid tumors was concerned. However, the drug has since been replaced with better alternatives owing to the many setbacks it faced in the treatment of tumors. As a result of intensive and extensive research on metal, N-heterocyclic carbene complexes have demonstrated remarkable improvement in their pharmacological characteristics.
Depending on the three metals highlighted therein (gold, silver, and platinum), the cytotoxic effects displayed can induce apoptosis in cancerous cells. The mode of cytotoxic action therefore largely depends on the choice of metal. It is therefore in the opinion of the author that the future of cancer treatment will have metal N-heterolytic carbene complexes as the fulcrum of its oscillation.
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