A14
Alkaloids
The use of alkaloids dates back to the dawn of civilization itself, with uses ranging from
important medicines to even poisons. One of the most famous appearances was in the death of
Socrates through the consumption of coniine-containing hemlock5. The way Coniine (2propylpiperidine) works is by antagonistically binding to the nicotinic receptor to cause muscle
paralysis. This paralysis eventually leads to respiratory failure, in which the subject usually dies
from lack of oxygen to the brain. Coniine was later synthesized by Albert Ladenburg in 1886 by
the chemical reaction below (Scheme 1).
Scheme 1. Coniine synthesis.
This reaction however, was by no means efficient and was later improved. Another alkaloid
made famous by Cleopatra was atropine. Atropine was found in henbane and was used to dilate
Cleopatra’s eyes to make her seem more alluring6. More modernly, chemical derivatives of
atropine are now used during eye exams to dilate the eye during observation.
Alkaloids are a diverse group of secondary metabolites found in many organisms, with
most being derived from plants. These organic compounds are created naturally through various
biosynthetic pathways and have an array of chemical structures. Although all alkaloids are
chemically different, they all share a basic principle in how they are defined. The most common
classification being, a cyclic organic compound containing nitrogen in a negative oxidation state,
often with the nitrogen contained within the heterocycle8. They are also commonly classified as
naturally occurring substances that are not vital to the organism that produce them. Due to these
vast arrays of chemical differences, alkaloids produce many neurological and physiological
effects to the organism that consume them. It is because of these effects, alkaloid-base plants
have become popular among humans, for uses good and bad.
Even though alkaloids have been used for centuries, the identification of the first
alkaloid didn’t come until 1806, when Serturner isolated morphine from the opium poppy,
Papaver somniferum9. Since its discovery, it has grown to be an important analgesic drug for
managing severe pain and suffering in the medicinal world. Its uses are most common in surgical
procedure in conjunction with anesthesia. Furthermore, it is also a drug of choice for those who
are terminally ill or suffer from cancer. Besides pain relief, Morphine is also known to cause
euphoria, one reason for its original popularity during the 19th century and even today. However,
its popularity today can be accredited to the street drug known as heroin.
Heroin was first synthesized by C.R. Alder Wright in 1874, when he decided to add two
acetyl groups to the molecule morphine in the synthetic process below (Scheme 2)4.
Scheme 2. Synthesis of heroin.
Wrights creation of the drug diacetylmorphine did not lead to further development, and wasn’t
popularized until its re-synthesis by Felix Hoffman. Hoffman determined that the acetylated
morphine was fast active and was about 2 times stronger that morphine itself. Bayer
Pharmaceutical products eventually released the drug under the name heroin, claiming it was a
non-addictive morphine substitute4. The later found that heroin was a quicker acting from of
morphine and was also broken down readily into morphine as well. With such a high potency,
heroin has been made illegal in the United States. Even with its ban, people still find a way to
buy heroin in its impure form, causing major health related risk all over the U.S. One of the most
common risks being the spread of blood based illnesses through the sharing of hypodermic
needles. Besides heroin, Morphine has many other derivatives such as Hydrocodone,
Oxycodone, and Codeine, all of which provide pain relief in some manner, with less potent and
addictive properties (Figure 1).
Figure 1. Morphine derivatives.
Another alkaloid that has been used in 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 for Europeans in colonial times, in which malaria ran
rampid. Due to quinine, europeans were able to colonize parts of Africa without succumbing to
the deadly effects of Malaria. It was also a “prime reason why African ceased to be known as the
white man’s grave”10. Its importance drove scientist to create a chemical synthesis of quinine,
but never took root due to high production cost. Today, Cinchona trees still remain as the only
economically practical source of quinine. However, recently quinine has been seen as a last
resort in the treatment of malaria, due to unpleasant side effects it may cause. It has readily been
replaced by the drug chloroquine, but is still used in poor countries because of quinine’s cheap
cost and easier availability10.
Quinine is not only used as an anti-malaria drug but also as flavoring in drinks, most
commonly tonic water, providing a slight bitter taste. Fix this sentence or citation style
Furthermore, quinine is also used in photochemistry as a fluorescent standard due to in relative
constant fluorescent quantum yield (wiki). Its absorption reading peak is at around 350 nm while
its fluorescent emissions peak is at around 460 nm10. Therefore when UV light is applied onto a
solution that contains quinine, such as tonic water, they glow 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 in which it works by stabilizing
microtubules so they are unable to breakdown during cell division. Taxol 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 the scarce resource it is harvested from.
With such limited availability, many are striving to synthetically produce the drug efficiently and
easily. However, with such a great synthetic challenge, it continues to be a very daunting task.
While one alkaloid might contribute to the saving of lives, this next alkaloid does not.
Nicotine contributes to just fewer than 500,000 deaths each year, through its role in
dependency, it is found in the leaves of 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 increase stimulation of the
reward receptors in the brain creating a sense of euphoria. This euphoric effect is one reason why
nicotine is so addictive, and is sometimes compared in likeliness to that of cocaine and heroin.
This addictiveness leads to increase use of tobacco and ultimately causes many health effects
later in life. To stop patients form smoking, 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, and is known to many
as caffeine. Caffeine is found in various seed, leaves and fruit of some plants, more specifically
from coffee beans and tea leaves. Caffeine acts a psychoactive stimulant, and is the most
consumed drug in the world. In the United states over 90% of all adult Americans 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, Thephylline
(Figure 2).
Figure 2. Caffeine metabolites.
The greater produced metabolite is Paraxanthine which causes elevated glycerol and fatty acid
level in the blood plasmids. Theobromine, which is the second most produced metabolite from
caffeine, causes blood vessels to dilate along with an increase in urine volume. The third and
least abundant metabolite of caffeine is Theophylline. Theophylline causes relaxation of smooth
muscles the bronchi and is commonly used as a treatment for asthma.
The chemical make-up of caffeine contains two fused rings, one being a pyrimidinedione
and 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. When too much
caffeine is consumed, it 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 hopes that one of those drugs
may actually change the world.
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.