Medicinal chemistry

Definition: Medicinal chemistry is the application of chemistry to the identification, synthesis, and preparation of pharmaceutical and medicinal compounds. Medicinal compounds come from a variety of sources and ideally serve a single purpose in their application as pharmaceuticals. The basic science of pharmaceutical materials is organic chemistry, which is utilized in the analysis and identification of biologically active materials, the preparation of those materials and their derivatives, and determination of their modes of function within biological systems. Synthetic organic chemistry is a very broad field of study and application and is the means by which chemical compounds are prepared in usable quantities.

Basic Principles

Medicinal chemistry is predicated on the fact that all life depends on a complex combination of chemical and biochemical processes. Within each process, each specific chemical material performs a specific function. Of course, the same material may be involved in several different processes, so there is also a great deal of overlap between systems. The interplay between all of the systems results in the individual living being, from the smallest and simplest of protozoa to the most complex and largest of animals and plants. The failure of a particular biological or biochemical system to function normally or the invasion and infection of the living being by other organisms can produce various states of illness in the individual; these resulting illnesses often requiring treatment with medicinal materials that will correct the biochemical problem or eliminate the invasive organisms. Medicinal chemistry generally refers to the identification and preparation of medicinal materials, based on the mode of action in which they are to be employed. This includes the preparation of both entirely synthetic compounds as well as compounds from natural sources, based on the principles of organic chemistry and biochemistry. This is very much a two-way process, as medical practitioners and researchers work to identify the nature and causes of medical and other errant conditions affecting people, animals, and plants. This knowledge initiates the research in medicinal chemistry to find and create the pharmaceuticals needed for the treatment of those conditions.

Core Concepts

The essential sciences of medicinal chemistry are synthetic organic chemistry, biochemistry, bioorganic chemistry, and biology, with analytical procedures being the most used and useful tool.

Synthetic Organic Chemistry. Synthetic organic chemistry is the branch of organic chemistry that deals with the theory and methodology of synthesizing specific molecules by controlled reactions of other molecules and compounds. It is founded on an in-depth understanding of the ways in which various functional groups within organic molecules can react with other materials and chemical agents. This is affected by the electronic structure of the particular compounds and functional groups, as well as by physical restrictions arising from the three-dimensional shapes of the reacting molecules. Much of the work of synthetic organic chemists involves finding ways around those restrictions in order to carry out a synthetic reaction that will yield a desired product having the correct molecular geometry. A great number of traditional and modern medicines have been obtained from natural plant and animal sources, and an untold number of such compounds are yet to be discovered. The natural products chemist—using the principles of organic and analytical chemistry—works to identify new compounds from plant and animal sources. It then falls to the synthetic organic chemist to find means of preparing those same compounds artificially so that the natural source need not be destroyed for harvesting of a compound. This is especially important when an identified material is available only in very small quantities, as was the case with the anticancer compound Taxol, obtained from the Pacific yew tree.

Bioorganic Chemistry. Bioorganic chemistry is also founded on the same functional group chemistry, but is concerned only with the limited number of functional groups that are involved in biochemical compounds and interactions. These are the materials of protein and tissue structures, energy transfer, ion transport, hormones, regulators, and the multitude of other known and unknown chemical components of living systems. It is estimated that there are more than one hundred thousand different chemical compounds involved in the various biochemical cycles that compose a living system, each behaving according to the fundamental principles of chemistry to perform a single role in the overall system. Bioorganic chemists work to identify the individual components of each system—some of which are present in mere picogram quantities—and to understand how each component attains, and is affected by, its unique three-dimensional structure. Proteins, for example, are composed of numerous amino acids in polymeric chains, linked together through the peptide bond structure in which the carboxylic acid function of one amino acid unit is bonded to the amine function of another amino acid unit. Since each amino acid contains both a carboxylic acid function and an amine function, the resulting protein is essentially a linear polyamide. However, due to the geometry of the amino acid groups and the electronic nature of the substituent groups attached to them, proteins acquire a complex three-dimensional shape that is determined by the identities of their component amino acids. Within the overall structure of the protein molecules are local regions that have a specific three-dimensional shape and electronic environment that enables them to interact only with molecules and parts of molecules that have a complementary shape and electronic structure. These materials, typically called enzymes, are responsible for carrying out essentially all biochemical reactions within the living system; each has a very specific function within that system. Understanding and identifying those functions is an essential component of medicinal chemistry, as the interactions of these materials with pharmaceutical compounds are essential to whether or not the pharmaceutical compound is effective.

Biochemistry. Biochemistry is the more general science of the chemical nature of living systems and includes the specialist field of bioorganic chemistry. Whereas bioorganic chemistry is concerned only with the reactions and interactions of organic molecules within living systems, biochemistry has the broader context that incorporates minerals and inorganic salts, gas exchange, ion transport mechanisms, energy transfer thermodynamics, cell structures, and kinetics of processes occurring in and between cells in an organism. There is, of course, a great deal of overlap between biochemistry and bioorganic chemistry; the extensive nature of the science of biochemistry has also led to other areas of specialization within that field. Biochemists study the chemical and physical principles behind the processes that occur within living systems, such as genetics, cell division, and cell structure formation. The ultimate goal of biochemical research is to know and define all of the various processes so that a complete understanding of living systems can be obtained, which in turn would allow an equal understanding of how living systems can fail and what to do for them medicinally when they do fail.

Biology. Biologists work to identify the various organic and physical systems within living organisms, the focus being on the macroscopic scale rather than the chemical scale. In the context of medicine this is in order to understand the reasons and manners in which those systems can malfunction so that they can be repaired through the use of the appropriate medicines and medical treatments.

Analytical Procedures. In all areas related to medicinal chemistry, analytical procedures are essential to the undertaking. In the operation of research that is chemical in nature, practitioners utilize the range of analytical devices and techniques typical of chemistry in general. This is especially true in the isolation and identification of new compounds isolated from natural sources. Such analysis allows the researcher to determine the molecular structure of the material, which is absolutely essential for any synthetic approach to preparing the material in quantity by artificial means. In medical practice, spectrometers and other analytical measuring devices are often utilized to determine the quantities of specific biochemical compounds present in living systems; this is a means to monitor the functioning of specific medicinal compounds. In the biological aspect of the field other devices, such as microscopes, are used to examine in detail the pathology of tissues that are affected by various conditions and the medicinal compounds developed for testing.

Applications Past and Present

Basis in Traditional Medicine. Every aspect of medicinal chemistry derives from the starting point of native herbal lore and the use of specific plant materials for the treatment of specific ailments. In many cultures this is a refined and well-respected art, if not an exact science. With the growth of workable chemical theories—still long before the development of the modern atomic theory and its ability to define molecular structures—scientists of the day began to isolate and identify various chemical principles from natural sources and to associate them with medicinal uses. One of the oldest of these was salicin, an anti-inflammatory agent isolated by the German chemists from the bark of the white willow tree. Today, this material is known as salicylic acid, the fundamental component of its acetylated derivative (aspirin, acetylsalicylic acid, or ASA). Due to its uncomplicated molecular structure, chemists of that time were able to prepare industrial quantities of this material using the empirical knowledge of synthetic chemistry that was available to them. Prior to this, medicinal compounds were obtained solely through extraction from their natural sources, and it was long believed that only living or organic systems could produce the materials that were extracted from them.

Early Organic Chemistry. This belief was disproven when, in 1828, a German chemist by the name of Friedrich Wöhler was able to synthesize urea, a naturally occurring organic material, from entirely nonorganic starting materials. The discoveries related to salicin and urea mark the beginning of modern medicinal chemistry. The science received its greatest boost, however, with the development of modern atomic theory, with its ability to describe molecular structures, reaction mechanisms, molecular geometries, and reaction energetics.

Perhaps the most important aspect of organic chemistry to be developed, in regard to medicinal compounds, was French chemist Louis Pasteur’s discovery of the property of chemical enantiomorphism—the ability to have mirror image forms—before turning his attention to the fermentation process and bacteriology. This is the property wherein a single compound can exist in two forms in which the corresponding molecular structures are identical in every way, except that one is the mirror image of the other. Such compounds also have identical physical and chemical properties, and are differentiated from each other only by their effect on plane-polarized light. When passed through a sample of each form, one will rotate the plane of the polarized light in the clockwise direction (to the right, or dextrorotatory), while the other will rotate the plane of the polarized light by the same amount in the counterclockwise direction (to the left, or levorotatory). It is a curious fact that all known biochemical systems use the levorotatory isomers exclusively and are unable to use the dextrorotatory isomers. Since all of the amino acids used in the formation of proteins are “optically active” in the levorotatory sense, this feature has had an enormous role in the development of living systems through evolutionary processes and in determining the overall shape of protein molecules and other biochemicals; it is also a vitally important aspect of the successful synthesis of all medicinal compounds.

Two Branches of Medicinal Chemistry. Partly because of the early relationship of organic chemistry to biological systems, the work of synthetic chemists has fallen into two basic camps with regard to medicinal chemistry. The first is the isolation and identification of compounds from natural sources, or natural products chemistry. This branch entails a heavy component of analysis following the recovery of a previously unknown material from a plant or animal source that may have been experiencing stress or a specific set of environmental conditions. Analysis is carried out to determine the exact molecular weight of the compound and to fully characterize its chemical and physical properties. This is achieved through various methodologies: Infrared spectrometric analysis is used to determine the types of functional groups that are present in the molecule; spectrometric analysis in the ultraviolet and visible range provides information about the nature of the bonds between atoms in the molecule. Nuclear magnetic resonance (NMR) spectrometry—based on different base nuclei, chiefly proton and carbon-13—is used to identify the bonding, three-dimensional orientations and positions of hydrogen and carbon atoms, respectively, within the molecular structure. Mass spectrometry is used to determine the exact molecular mass of the compound, as well as to provide structural information from the fragmentation patterns that are observed, although NMR is by far the more powerful technique for obtaining structural information. Numerous other properties can also be tested, but these methods are the primary analytical techniques. These methods are also routinely applied in monitoring the progress of reactions and determining their effectiveness.

The second branch, which is also the primary focus of medicinal chemistry, is synthetic organic chemistry. In this discipline, the chemist draws upon the wealth of documented knowledge about various reactions and the conditions under which they are carried out. This provides the basic steps for the synthesis of specific compounds, as the synthetic chemist can be assured of what to expect when the same or very similar reactions are carried out in the same way. On numerous occasions, however, a reaction procedure will not work, or is unsuitable for other reasons, and new synthetic methods must be sought. Research in synthetic methods is an extensive field of synthetic organic chemistry in its own right. Generally, the goal of synthetic methods research is to find a means of producing a specific molecule or part of a molecule cleanly and efficiently (without undesirable side products) or to prove the viability of a previously untried material in carrying out a specific type of reaction.

Medicinal Chemistry Research. As medicinal chemistry is inextricably linked to biochemistry and biology—and the ultimate end of pharmaceutical materials is to function in harmony within living systems so as to ameliorate or cure a pathological condition—the range of materials involved in medicinal chemistry is greatly extended. In the twenty-first century a great deal of research is carried out in the field of molecular cell biology, in which the interactions of various compounds with the materials of genetics and cell structures is the focus. Here as well, a great deal of analysis and testing is carried out, employing several methodologies that are relevant to chemistry in general and some that are unique to biological systems. Electrophoretic separations of biological components, particularly of DNA and other proteins, is one of the most generally applicable techniques and provides a unique characterization for biological compounds. Technological advances beyond the electron microscope also play a role in biological analysis, though they are limited to surface analysis at the atomic level. Such devices as the scanning tunneling microscope and the atomic force microscope now make it possible for researchers to examine cell structures such as viruses and molecular structures such as DNA more closely than has ever been possible. They also enable the manipulation of individual atoms, allowing distinct atomic-scale structures to be constructed and tested.

Social Context and Future Prospects

Medicinal chemistry holds a unique place in applied science, not so much because of what it does, but for the potential of its side effects. The ultimate goal of medicinal chemistry is the production of pharmaceutical compounds and materials that will save the lives of people, animals, and even plants. One obvious outcome of this is that the human population will increase at a faster rate than it would otherwise, placing ever greater pressure on the natural resources and wild areas of the planet. At the same time, however, the ability to synthesize pharmaceutical compounds obtained from those same natural sources actually works to alleviate the pressure placed on them through harvesting of those compounds, thus helping to preserve the natural resources. It is an odd balancing act, and no other science holds a similar place in human society. There are a great many social hurdles that are encountered by medicinal chemistry as a science, not the least of which are its roles in the controversial science of stem cells and litigation arising from the side effects of various pharmaceuticals. Regulations governing the release of new pharmaceuticals will likely become even more restrictive over time, which will in turn increase the costs of pharmaceuticals in general. This alone would ensure that synthetic organic chemists will always have a valuable role to play in the development of syntheses that are effective at producing complex compounds at the lowest possible cost.

About the Author

Richard M. Renneboog holds a master’s degree in synthetic organic chemistry from the University of Western Ontario. He subsequently spent a number of years working in the Department of Chemistry at University of Alberta attempting to synthesize nonprotein analogs for the active site of an enzyme. He currently works independently as a technical consultant and writer in Canada.

Bibliography

Alessio, Enzo. Bioinorganic Medicinal Chemistry. Weinheim: Wiley, 2011. Print. Presents a sound introduction to the concepts of bioinorganic chemistry, including radiopharmaceuticals. Also discusses the functions of physiology dependent not only on organic chemistry, but on numerous inorganic materials that are also essential components of biological systems.

"Chemists and Materials Scientists." Occupational Outlook Handbook, Bureau of Labor Statistics, 29 Aug. 2024, www.bls.gov/ooh/life-physical-and-social-science/chemists-and-materials-scientists.htm. Accessed 7 Nov. 2024.

Corey, E. J., Barbara Czako, and Laszlo Kurti. Molecules and Medicine. Hoboken: Wiley, 2012. Print. An illustrated book for a general readership discussing the chemistry behind numerous commonly encountered pharmaceutical compounds.

Dewick, Paul M. Medicinal Natural Products: A Biosynthetic Approach. Chichester: Wiley, 2009. Print. Provides a thorough introduction to the biochemical pathways and mechanisms by which various classes of compounds, including various hydrocarbons, alkaloids, peptides, proteins, and carbohydrates, are manufactured in plants and other living organisms.

Foye, William O., and Thomas L. Lemke. Foye’s Principles of Medicinal Chemistry. 6th ed. Baltimore: Lippincott, 2008. Print. Written for advanced students, pharmacists, and practitioners of medicinal chemistry. Approaches the subject in great detail, using case studies and an emphasis on patient-focused pharmaceutical care.

Thomas, Gareth. Medicinal Chemistry: An Introduction. 2nd ed. Hoboken: Wiley, 2011. Print. Provides a thorough introduction to the science of medicinal chemistry without assuming prior knowledge in any area from basic principles through advanced combinatorics and pharmacokinetics.