Cancer is a cellular disease which arises from defects in the cellular mechanisms that control cell division thus resulting in the accumulation of large cell mass due to uncontrolled cell division. Cancer treatment is majorly based on chemotherapy, radiotherapy and surgery or a combination of either of the three. Most recently gene therapy approaches have also been used. Cancer treatment however continues to face a challenge of multiple drug resistance, non-specificity of the drug molecules as well as cytotoxic and cytostatic drugs. Advancement in chemistry has since give insight into discovery of new drugs that are less toxic and more efficient. This paper discusses the application of chemistry in anticancer drugs discovery. In the paper, it is shown that chemistry has greatly contributed to the discovery of new drugs through synthetic drugs and computer aided drug design approaches. As such, it is clear that more research need to be done in order to characterise more useful molecules in cancer drug discovery.
Keywords: Cancer, Chemistry, Anticancer
Survey the various contributions made by Chemistry to anticancer drug discovery, giving key examples of some important milestones and complementary technologies
Introduction
Cancer is a medical term that refers to multiple diseases of the cell characterised by defects in the mechanisms that regulate cell division. The defects generally targets key genes involved in regulating cell division. As a result, uncontrolled cell division, growth, and spreading of cells sets in. As a result of this defects, a primary tumor, which is basically a mass of cells that have detrimental effects to the adjacent cells. The tumor cells may as well spread to other parts of the body through a mechanism known as metastasis. Metastasis is linked to 90 % cancer-related deaths. Currently, cancer is known to contribute to 13 % of the global mortality rate with the incidences steadily increasing among the elderly populations mostly in the developed countries (Avendano and Menéndez, 2008a).
The onset of molecular biology led to a detailed understanding of the mechanism of cancer development. It is now known that cancer arises from genetic defects within the genes of the affected cells. Generally, the cancer development process also known as Tumorigenesis is a stepwise process that involves the procedural accumulation of mutations in two categories of genes responsible for cancer development. These are the oncogenes (cancer-causing genes) and the tumor suppressor genes which are a group of genes that control cell division. These genes are subjected to various forms of mutations such as point mutations, chromosomal aberrations, amplifications and deletions as well as changes targeting the chromatin structure which greatly determines gene expression (Avendano and Menéndez, 2008b). Changes targeting the chromatin structure include histone acetylation and aberrant DNA methylation (addition of a methyl group to a DNA molecule) (Avendano and Menéndez, 2008a).
For a long time, cancer treatment was based on radiotherapy, systematic chemotherapy and surgery or both. These treatment methods are aimed at destroying the cancerous cells. However, these treatment options have minimal success rates and most patients are not completely cured (Avendano and Menéndez, 2008a). As such they merely obtain a prolonged lifespan or none at all. Chemotherapy drugs mostly function by inhibiting the process of cell division among the cancer cells thus resulting in death. They, however, face a challenge in that most of them are cytotoxic and/or cytostatic. Owing to this challenge and the advanced knowledge in cancer biology, more advanced anticancer drugs have been developed (Avendano and Menéndez, 2008a). Chemistry has been a key player in the anticancer drugs discovery and development from the onset of cancer therapy. This paper discusses the contributions made by chemistry to the discovery of anticancer drugs.
Chemistry contributions in the discovery of anticancer drugs
From the onset of the 1950s, Chemistry has made a great contribution to the development of anticancer drugs through the process of in silico screening of compounds using a wide range of cancer cell lines. The reasoning behind the use of cytotoxic anticancer drugs was based on the apparently high sensitivity of rapidly diving cells to compounds as compared to the normal cells. Later on, cytotoxic compounds that specifically target the minor and major grooves of the defective DNA molecules were developed. Despite this, a challenge of non-specificity of this drugs still remained. As such, it became necessary to develop more specific anticancer drugs which incorporated the use of monoclonal antibodies targeting specific markers expressed on the tumor cell surfaces. Rational drug design requires a clear understanding of the three-dimensional structure of these unique surface antigens expressed on the cancer cells. When absent, a homology approach may be adopted through the use of an experimental structure of analogous proteins. The development of this lead compounds into ‘druggable’ compounds requires a proper understanding of their chemical properties such as reactivity and solubility as these properties greatly determine their absorption as well as metabolism. It is thus appropriate to have a structural understanding of metabolic enzymes as a leeway to improving the effectiveness as well as the patients’ tolerance to anticancer drugs. For this to be realised, in silico chemistry techniques are widely applied.
Humans have a long history of using natural products in disease management. In particular, most cultures use plant-based natural products for medicinal purposes. The development of chemistry enabled the characterisation of bioactive compounds in plants where their structure, pharmacodynamics and pharmacokinetics were unravelled. It is currently undisputed that the use of natural products is a key aspect in drug discovery owing to the inability of substitute drug discovery methods to produce enough lead compounds in key areas including metabolic diseases such as cancer (Mathur and Hoskins, 2017). Understanding the structure of the bioactive compounds in the natural products has greatly contributed to the concept of computer aided drug design which is greatly applied in synthetic chemistry.
The discovery of key bioactive molecules through X-ray crystallography and Nuclear Magnetic Resonance (NMR) spectroscopy has given rise to a number of potential drug molecules which are subsequently deposited in an open database (http://www.rcsb.org). Computational chemists and other researchers in the field of anticancer drug discovery freely access this information. They ultimately use it in studying the interaction between different protein molecules or interaction between the protein molecules and ligands. This interaction is key to the drug and target binding during drug development. Computer-aided drug design has led to a large milestone in the discovery of anticancer drugs. This is owing to the understanding of the 3-D structure of the chemical compounds which ultimately allows researchers to rationally develop drugs with higher affinity in a computer aided manner. The application of structure based drug design has been reported in the recent years. For instance, structure-based pharmacophore modelling has made it possible to identify inhibitors of p53 upregulated modulator of apoptosis (PUMA). PUMA, which is a pro-apoptotic protein, is regulated by the p53 protein. Its inhibition results in apoptosis (programmed cell death) that is associated with increased cancer development risk (Prada-Gracia, Huerta-Yépez and Moreno-Vargas, 2016).
Liu et al. (2010), reported through a combinatorial computation approach were able to discover potential antagonists of the insulin-like growth factor-1 (IGF-1R). The (IGF-1R is a member of the Tyrosine Kinase family of proteins that play a key role in cell proliferation, growth and death. Another example is the development of tubulin inhibitors (Chiang et al., 2009). Tubulins are cellular molecules involved in the progression of cell division through a process known as tubulin polymerization. They are thus key targets for anticancer drugs. Initially, naturally occurring compounds like colchicine were used as tubulin inhibitors (Prada-Gracia, Huerta-Yépez and Moreno-Vargas, 2016). They, however faced a challenge of rapid resistance, low bioavailability and significant toxicity. This challenge has been met with the computer-aided drug design based on a prior understanding of the key molecules (Prada-Gracia, Huerta-Yépez and Moreno-Vargas, 2016).
Lastly another molecule known as I-Kappa-B Kinase- β (IKK-β) inhibitor also been designed based on computational chemistry. This molecule inhibits a key pathway involved in cellular signalling thus inhibiting the development of cancer (Prada-Gracia, Huerta-Yépez and Moreno-Vargas, 2016).
Conclusion
In conclusion, chemistry has made it possible for researchers involved in drug design and discovery to determine key drug molecules that are vital in the treatment of cancer which commands a high percentage of global mortality index. It is also, evident from the research findings that in order to design a drug, understanding the target molecules’ structure is essential.. This should involve characterising the potential lead compounds that will ultimately be used in drug design and development. The availability of various structures has since made it easier to develop various drugs. This has speeded up the process of drug discovery and development hence lowering the price of drugs on the shelves as lesser money is involved in the process of drugs discovery and development. It is thus necessary for more research to be carried out on the previously used medicinal plants with potential bioactive properties.
The use of computers in the drug development process would not have been possible without the contribution of early chemistry techniques such as X-ray Crystallography and NMR spectroscopy. These early developments in chemistry gave provided a basic foundation on the structure of bioactive compounds which has since been applied in computational chemistry. As such, chemistry is a key player to the process of drug discovery and design which cements the need for further research in the chemical structure of biomolecules, their metabolism, reactions and absorption.
References
Avendano, C. and Menéndez, J. C. (2008a) Medicinal Chemistry of Anticancer Drugs. First Edit. Amsterdam: Elsevier. doi: 10.15713/ins.mmj.3.
Avendano, C. and Menéndez, J. C. (2008b) Medicinal Chemistry of Anticancer Drugs. Second Edit. doi: 10.1016/B978-0-444-52824-7.X0001-7.
Chiang, Y.-K. Kuo, C.C., WU, C., Coumer, M. S., et al. (2009) ‘Generation of ligand-based pharmacophore model and virtual screening for identification of novel tubulin inhibitors with potent anticancer activity.’, Journal of medicinal chemistry, 52(14), pp. 4221–33. doi: 10.1021/jm801649y.
Liu, X., Xie, H., Luo, C., Tong, L., et al. (2010) ‘Discovery and SAR of thiazolidine-2,4-dione analogues as insulin-like growth factor-1 receptor (IGF-IR) inhibitors via hierarchical virtual screening’, Journal of Medicinal Chemistry, 53(6), pp. 2661–2665. doi: 10.1021/jm901798e.
Mathur, S. and Hoskins, C. (2017) ‘Drug development: Lessons from nature (Review)’, Biomedical Reports, pp. 612–614. doi: 10.3892/br.2017.909.
Prada-Gracia, D., Huerta-Yépez, S. and Moreno-Vargas, L. M. (2016) ‘Application of computational methods for anticancer drug discovery, design, and optimization’, Boletin Medico del Hospital Infantil de Mexico. Hospital Infantil de México Federico Gómez, 73(6), pp. 411–423. doi: 10.1016/j.bmhimx.2016.10.006.
