In the previous chapter, we discussed the first example of a drug being isolated
from natural sources so that it could be purified and administered as treatment
instead of being limited to the plant itself, which was a huge step forward for science.
That drug was morphine, an alkaloid isolated in Germany in 1804. Today morphine is still an
important drug, as well as a source of more active semisynthetic analgesics. There are
countless other examples of important alkaloids that were subsequently isolated from other plants,
and this activity is still ongoing, to some extent, even in the 21st century. We don’t
have time to tell all of these stories, but we absolutely must tell just one more. The most
interesting and multifaceted story in the alkaloid world centers on the isolation of quinine.
Before we get into the meat of the story, we need to discuss another infectious disease that,
like smallpox, has probably killed billions of people in the history of mankind, and continues
to be a major problem in the Third World. This disease is malaria. Though it remained mysterious
even in the early 19th century, it is now known that the disease is caused by a microorganism,
Plasmodium falciparum, which is transmitted through the bite of
an infected Anopheles mosquito. The disease probably crossed over from monkeys into humans
about 10,000 years ago, and found fertile grounds among the first agricultural settlements.
The disease derives its name from the Italian word for “bad air”, as indeed it was a prevalent
disease in Italy during the Roman Empire, when it was actually referred to as “Roman fever”. The
Latium area around Rome was full of swamps, and most physicians associated the disease with the
bad swamp air, a way of thinking that was clearly influenced by miasmatic theory. Of course, it was
later discovered that it was simply that swamps were the perfect breeding grounds for mosquitos.
Malaria is characterized by intermittent fevers, due to the complex life cycle of
the Plasmodium microorganism. Patients can slowly recover, but may be left lethargic and anemic for
years. Furthermore, effects can still continue beyond this, because a form of the pathogen can
become lodged in the liver. In certain cases, a blood clot may form in the patient’s brain,
and in these acute cases the disease is lethal. Nowadays, malaria is endemic in Africa, and also
in parts of Southeast Asia. In 2018 there were 228 million cases of the disease, resulting in
405,000 deaths. Even with modern medicine, the mortality rate is still a threatening 0.2%,
and it was of course much higher 2,000 years ago. The prevalence and mortality were so severe
that it is often speculated that the disease was a major factor causing the fall of Rome in 476 CE.
Jesuit missionaries from Europe visiting South America in the 17th century found that in Peru,
natives used the bark of the tree Cinchona officinalis, which was called “quina-quina” by the
locals, to cure patients from recurring fevers, which the missionaries identified as malaria.
The Jesuits were responsible for bringing the bark to Europe, where it was enthusiastically adopted.
The tree Cinchona officinalis grew on the eastern slopes of the Andes,
mostly in Peru, between the altitudes of 1,500 and 2,900 meters, and rather predictably,
European demand led to extensive harvesting and the gradual destruction of the Cinchona habitat.
After 1681, the bark was universally indicated in Europe as the first treatment against malaria,
and Spain had the worldwide monopoly, which resulted in shortages of the bark.
As Peru became an independent country early in the 19th century, there was a strong focus on keeping
and exploiting the monopoly of the Cinchona bark, and the government enacted legislation banning the
export of Cinchona seeds and saplings, with such activities being punishable by death.
Undeterred, the British sent an expedition to Peru, and returned with plenty of seeds to start
a plantation in Ceylon, or present-day Sri Lanka. This was a very challenging project, due to the
lack of climatic coherence between the slopes of the Andes and the tropical climate of Ceylon,
and it was not immediately successful. A British trader, Charles Ledger, sold some seeds to Dutch
explorers, and the Dutch had more luck with them, establishing large plantations in Java, Indonesia.
As we discussed previously with the poppy pods and morphine, early in the 19th century,
European scientists attributed the effects of Cinchona bark extracts to the presence of active
chemical substances in the bark and no longer to some magical properties held by the plant itself.
After Sertürner’s demonstration that alkaloids tend to be basic and precipitate from alkaline
solutions, it occurred to Joseph Gay-Lussac that the elusive component of the Cinchona bark was an
alkaloid. He asked the Ecole de Pharmacie in Paris to start working on the substance, and in 1820
two young chemists, Pierre Pelletier and Joseph Caventou, extracted the bark with alcohol,
and then diluted and basified the extracts, precipitating a gummy mass, which they called
“quinine”, although it contained small amounts of other alkaloids, such as cinchonine.
The original samples by Pelletier and Caventou are now exhibited in London’s Science Museum.
This substance was immediately used by French physicians, who proved that it was
effective in curing malaria fevers, and they quickly developed a suitable dosing regimen.
Only ten years after its isolation, quinine was produced industrially, also by Pelletier and
Caventou, and it became the first-line treatment against malaria, saving millions of lives.
Immediately, the extraction of quinine from Cinchona trees took off worldwide, as there
was no patent issued on the process, and by 1850 or so, quinine was in short supply. The substance
was considered one of the top strategic assets determining the future prosperity of an empire.
Africa was a huge continent waiting to be explored and conquered, but without protection
from malaria, the plan could not work. The Dutch had the most reliable supply of the drug,
and this was probably one of the keys to their successful forays into South Africa.
There was considerable interest in France and Great Britain to prepare the drug by alternative
means, and in 1851, chemists were promised a huge prize by the French Society of Pharmacy
if they could present half a pound of synthetic quinine. Nobody claimed the prize.
Just to elucidate how absurd the idea was that organic chemists might be able to synthesize
quinine in the 1850s, one has simply to remark that chemists did not yet know
how atoms were bound together to form complex organic molecules. That theory had to wait for
Dutch chemist Jacobus van ’t Hoff, who proposed the modern stereochemical theory
in 1874. He had conceived of this idea while still a graduate student, and published it in 1875.
Van ‘t Hoff was the first recipient of the Nobel Prize for chemistry in 1901,
which was awarded for his work on the theory of chemical solutions.
Truly, the only thing chemists could determine in 1850 was how much carbon, how much oxygen, how
much nitrogen, and how much hydrogen was present in a substance, which can be used to discern the
molecular formula of a compound, or the number of atoms of each element that are present.
Elemental analysis, as this is called, was a known technique at that time, but unfortunately, the
molecular formula of a substance says very little about how the atoms are bound to each other in a
chemical structure, which is of supreme importance to its bioactivity. Totally unaware of this fact,
the “theory of types” in those days assigned paramount importance to the molecular formula.
August Wilhelm von Hoffmann was the German director of the new Royal College of Chemistry
in London. He had decided to try to synthesize quinine, and determined its molecular formula
as C20H22N2O2, which was incorrect, as it actually has two more hydrogen atoms than this.
He noticed that the formula was similar to what could be produced arithmetically by combining
two molecules of α-naphthylamine, a product isolated from tar, plus two molecules of water,
and he proposed a synthesis of quinine by somehow “hydrating” naphthylamine. Of course,
even a non-chemist can look at what we now know to be the structures of quinine and α-naphthylamine,
and realize that there was no chance that Hoffmann was going to make quinine with this strategy,
as the structures are completely unrelated. But ignorance is bliss, and luck sometimes
helps the oblivious, as we will see in a moment. Hoffmann’s idea, as absurd as it seems today,
was deemed reasonable in those days, and he received funding for his research.
In 1854, the correct molecular formula for quinine was published by another famous German professor,
Adolf Strecker, and this pretty much shot down the whole fantastic theory of hydrating naphthylamine,
because there were two additional hydrogen atoms, but no additional oxygen atom. The
sponsors of the research were getting restless and unhappy about the lack of results.
One of the new students assigned to the project was William Perkin, who was later to become one
of the greatest chemists of all time. In 1856, however, he was only 18 years old,
enthusiastic but not yet truly knowledgeable. He had entered college at 15, already a professional
violinist and leaning towards a career in music, but his father wanted him to become something more
practical like an architect. Instead, Perkin’s other passion was chemistry. He had built a lab at
home, and since he had received the project before the Easter vacation but could not wait to start,
he decided to begin the research at home in East London. His new theory was that oxidation of
N-allyl toluidine ought to give something called a dimer with the same constitution of quinine.
Unfortunately, N-allyl toluidine is nothing like quinine, and his experiments were not successful.
Now here comes the interesting part. The first oxidizing agent Perkin used in his attempts
was potassium dichromate. All that he got from this attempted oxidation
was a red goo that soiled his white apron so badly that he could not get it off, even by washing with
detergents in boiling water. It did not even fade upon exposure to sunlight. Although this
result was not related to his initial goal, Perkin learned to make this red substance reproducibly
and called it aniline purple, later referred to as mauvein. His supervisor was not impressed,
but Perkin persuaded his father to go into business with him to mass produce the new dye,
and in 1857 they opened a little factory. Prior to Perkin’s work, dyes were prepared
by squeezing natural dyes out of vegetables or insects. The resulting dyes were expensive,
difficult to produce, and lacked the brilliance we later came to expect from artificial dyes.
When Queen Victoria wore dresses dyed with Perkin’s mauveine,
the reaction was immense. The Perkin family business became a worldwide sensation, and
the ensuing period was named “the mauve decade” throughout Europe. Everyone wanted that dye.
The structure of Mauvein A was elucidated a century later by extensive analysis using nuclear
magnetic resonance, or NMR, an indispensable tool used by organic chemists. As you can see,
the structure is nothing like quinine, but it was a stunning success nevertheless.
Quinine finally yielded to total synthesis for the first time almost a century later, in the labs of
Professor R. B. Woodward at Harvard, in 1944. But despite the achievement, it was not a synthesis
that could compete economically with extraction of quinine from tree bark. Quinine is still produced
by extraction from a number of trees, and has a worldwide market of over 300 tons per year,
with a value of almost 1 billion dollars per year. However, it is no longer the only anti-malarial
drug, and not even the most important one. Perkin’s mauvein gave rise to the industry
of aniline dyes. He sold his business in 1873 to start an academic career,
in which he was very successful, discovering a chemical reaction that bears his name.
To take advantage of the new demand, large companies opened up, especially in Germany,
employing hundreds of chemists to develop new dyes by chemical reactions. The companies that
arose around the end of the 19th century are still household names in the world of chemistry.
These are BASF in Ludwigshafen, now a huge chemical company; Hoechst in Frankfurt,
which is now Sanofi-Aventis, a large Pharma company; and Bayer in Leverkusen, now another
large Pharma company. These all jumped into the new business, and by the end of the 19th century
the dye market was saturated. All natural dyes had been phased out, replaced by a host of shiny
new synthetic ones, and the market for the German giants began to dry up. However, having so many
chemists at their disposal, the German companies decided to use them to make synthetic drugs,
and in this way, the modern era of drug synthesis began around the turn of the 20th century.
Rather incredibly, one can justifiably say that young William Perkin, simply by
soiling his apron with red gunk, enabled the birth of the modern pharmaceutical industry,
whose first steps we will discuss shortly. But before we jump into the pharma business,
we must discuss another revolution that was also occurring during the late part of the
19th century, a revolution that was much more important than the development of red dyes.
This was the birth of microbiology, and the understanding that most of
the deadly diseases which plagued mankind were caused by heretofore undetected little bugs,
or microorganisms. Their discovery would shed light on diseases like smallpox and malaria which
we have already discussed, so let’s move forward and see how these realizations were to unfold.