A14
Alkaloids
Alkaloids are a diverse group of secondary metabolites found in many
organisms. These organic compounds, most of which are derived from plants, are
created naturally through various biosynthetic pathways and have different chemical
structures. Although alkaloids are chemically different, they all share a basic definition.
Alkaloids are commonly classified as a cyclic organic compounds containing nitrogen in
a negative oxidation state, often with the nitrogen contained within a heterocycle8. They
are also recognized as naturally occurring substances that are not vital to the organism
that produces them. A vast array of chemical differences allow alkaloids to produce
many neurological and physiological effects to the organism that consumes them.
These effects naturally gave rise to the popularity of alkaloid-base plants among
humans for both good and bad uses.
Alkaloid use dates back to early civilization, varying in use from important
medicines to even poisons. One of the most famous instances of alkaloid use was in the
death of the famous philosopher Socrates through the consumption of coniinecontaining hemlock5. Coniine (2-propylpiperidine) works by antagonistically binding to
the nicotinic receptor which causes muscle paralysis. This paralysis eventually leads to
respiratory failure, which then leads to death due to the lack of oxygen supply to the
brain. In 1886, Albert Ladenburg was able to synthesize coniine in the lab through the
chemical reaction depicted below.
This reaction however, was by no means efficient and was later improved. Another
alkaloid, atropine, was made famous by Cleopatra. Atropine was found in henbane and
was used to dilate Cleopatra’s eyes to make her appear more alluring6. In modern
times, chemical derivatives of atropine are used during eye exams to dilate the eye
during observation.
Even though alkaloids have been used for centuries, the first alkaloid was not
identified until 1806 when Serturner isolated morphine from the opium poppy, Papaver
somniferum9. Since its discovery, morphine has grown to be an important analgesic
drug for managing severe pain and suffering in patients. It is most commonly used in
surgical procedures in conjunction with anesthesia. Furthermore, it is also a drug of
choice for treating those who are terminally ill or those who are suffering from cancer.
Aside from providing pain relief, morphine was also known to cause a sense of
euphoria. This is the reason for its original popularity during the 19th century and even
today. However, its modern-day popularity can be attributed to the street drug heroin.
Heroin was first synthesized by C.R. Alder Wright in 1874, when he decided to add
acetyl groups to the molecular structure of morphine in the synthetic process illustrated
below4.
Wright’s creation of the drug diacetylmorphine did not lead to further development and
the drug was not popularized until a new synthesis pathway was discovered by Felix
Hoffman. Hoffman determined that the acetylated morphine was fast acting and was
about two times more potent than morphine itself. Bayer Pharmaceutical products
eventually released the drug under the name Heroin, claiming it was a non-addictive
morphine substitute4. It was later found that heroin was a quicker-acting form of
morphine and was also broken down readily into morphine as well. Because of its high
potency and notoriety for inducing severe drug dependence, heroin has been made
illegal in the United States. Even with its ban, people still find a way to buy heroine in its
impure form, causing a major health risk in the United States. The most common risk
associated with heroin use is the spread of blood-borne illnesses through the sharing of
hypodermic needles. Aside from heroin, morphine also has many other derivatives such
as hydrocodone, oxycodone, and codeine, all of which provide relief in some manner
with less potency and with less addictive properties.
Another alkaloid of great importance in the field of medicine is the compound
quinine. Quinine is found in the ground bark of cinchona trees and has been used as a
treatment for malaria since the early 17th century. It proved to be a vital drug for
Europeans in colonial times when malaria was rampant. Quinine allowed Europeans to
colonize parts of Africa without succumbing to the deadly effects of malaria. It was also
the “prime reason why Africa ceased to be known as the white man’s grave”10. The
importance of quinine inspired scientists to find a way to chemically synthesize quinine
but this never took root due to the high cost of production. Today, cinchona trees are
still the only economically practical source of quinine. Recently, quinine has been
considered a last resort in the treatment of malaria because of the unpleasant side
effects it may cause. Quinine has readily been replaced by the drug chloroquine, but it
is still used in poor countries where quinine is much cheaper and more easily
available10.
Aside from its use as an anti-malaria drug, quinine is also used as flavoring in
drinks, most commonly tonic water, because it provides a slight bitter taste.
Furthermore, quinine is used in photochemistry as a fluorescent standard due to its
relatively constant fluorescent quantum yield (wiki). Its absorption reading peaks around
350 nm while its fluorescent emissions peak around 460 nm 10. When UV light is shone
onto a solution that contains quinine, for instance tonic water, it glows a cyan blue.
Early in the 20th century, cancer became an important topic of research in
medicine. With little traction in finding a cure, one alkaloid created the first
developmental stride in providing hope to the masses. Paclitaxel was discovered in
1967 by Monroe E. Wall and Mansukh C. Wani from the National Cancer Institute. They
isolated the drug from the pacific yew tree, Taxus brevifolia, and named it Taxol6. Taxol
is a mitotic inhibitor which works by stabilizing microtubules in the cell so that they are
unable to break down during cell division. It is approved in the UK for the treatment of
ovarian, breast, lung, and other cancers, but is very expensive because of its limited
availability. This limited availability is due to scarcity of the resource it is harvested from.
With such limited quantities, many are striving to synthetically produce the drug
efficiently and easily. The challenge of synthesizing Taxol in the lab continues to be a
very daunting task.
While some alkaloids may save lives, another widely known alkaloid does the
complete opposite. This alkaloid contributes to almost 500,000 deaths each year
because of the dependency it induces in individuals. This alkaloid is nicotine, and it is
found in the leaves of the plant tobacco. Nicotine contains two nitrogen rings, one of
which is pyrrolidine and the other pyridine7. These chemical groups help nicotine bind to
the nicotinic acetylcholine receptor and act as an agonist. This causes increased
stimulation of the reward receptors in the brain, creating a sense of euphoria. This
euphoric effect is one of the reasons why nicotine is so addictive and is sometimes
compared in likeness to that of cocaine and heroin. This addictiveness leads to
increased tobacco use, and it ultimately causes many negative effects on one’s health
later in life. To stop patients form smoking tobacco, a nicotine replacement regiment can
be implemented in which gum, patches, or lozenges are used to slowly eliminate
nicotine dependency.
Lastly, there is one alkaloid that is digested by millions every day. It is known to
many as caffeine. Caffeine is found in various seeds, leaves, and fruit of some plants,
more specifically from coffee beans and tea leaves. Caffeine acts as a psychoactive
stimulant in the body. It is the most consumed drug in the world. Over 90% of all
American adults consume caffeine on a daily basis. Once ingested, caffeine is
metabolized in the liver by the cytochrome P450 oxidase enzyme into three different
metabolites: paraxanthine, theobromine, and theophylline.
Paraxanthine is the metabolite produced in greatest amounts. It causes elevated
glycerol and fatty acid levels in the blood. Theobromine, the second most produced
metabolite from caffeine, causes blood vessels to dilate and also causes an increased
urine volume. The third and least abundant metabolite produced from caffeine is
theophylline. It causes relaxation of smooth muscles in the bronchi and is commonly
used as treatment for asthma.
The chemical structure of caffeine is comprised of two fused rings, one being a
pyrimidinedione and the other an imidazole. It is usually synthesized in plants from the
purine nucleotides adenosine monophosphate (AMP), guanosine monophosphate
(GMP), and inosine monophospate (IMP)3. With its close resemblance to adenosine,
caffeine is able to block the adenosine receptors in the brain, stopping the suppression
of activity in the central nervous system. In too large doses however, caffeine begins to
inhibit the GABA receptor which results in insomnia, anxiety, and increased heart
rate/respiration.
With such variability in how they affect the human body, alkaloids have become
an important part of medicinal research. This continuously growing library of plant
constituents provides models for the synthesis of modern synthetic drugs. With the help
of plant extract screening programs, new drugs are continually being discovered, in the
hopes that one of those drugs may change the world one day.
Work Cited
1. Achan, Jane, et al. "Quinine, an old anti-malarial drug in a modern world: role in the
treatment of malaria." Malar J 10.144 (2011): 1475-2875.
2. "Alkaloid." Wikipedia. Wikimedia Foundation, 02 July 2014. Web. 09 Feb. 2014.
3. "Caffeine." Wikipedia. Wikimedia Foundation, 02 Apr. 2014. Web. 06 Feb. 2014.
4. "Heroin." Wikipedia. Wikimedia Foundation, Web. 09 Feb. 2014.
5. Kutchan, Toni M. "Alkaloid Biosynthesis -The Basis for Metabolic Engineering of
Medicinal Plants." The Plant Cell 7.7 (1995): 1059.
6. Nicolaou, K. C., et al. "Total synthesis of taxol." Nature 367.6464 (1994): 630-634.
7. "Nicotine." Wikipedia. Wikimedia Foundation, Web. 09 Feb. 2014.
8. Pelletier, S. "The Nature and Definition of an Alkaloid." Toxocology. N.p.: n.p., n.d.
27-31. Web. 09 Feb. 2014.
9. Roberts, Margaret F., and Michael Wink, eds. Alkaloids: biochemistry, ecology, and
medicinal applications. Springer, 1998.
10. "Quinine." Wikipedia. Wikimedia Foundation, 02 July 2014. Web. 09 Feb. 2014.