Drugs from natural sources

Natural products and the drugs they gave us

A natural product is a chemical compound made by a living organism, such as a plant, a mould, a bacterium or a marine animal. Many natural products have a biological effect on the human body. A drug is a substance that changes how the body works. A medicine is a drug used to prevent, treat or cure disease.

Plants cannot run away from predators or germs, so many of them make chemicals that defend them. Some of these chemicals also work on human cells. That is why plants have been a rich source of medicines.

Aspirin: from willow bark to tablet

Willow bark contains salicin. In the body, salicin is converted to salicylic acid, which relieves pain and reduces fever. The problem is that salicylic acid irritates the lining of the mouth and stomach. In 1897 chemists at the company Bayer made a modified version, acetylsalicylic acid, which is much better tolerated. We call it aspirin.

The change is small: the phenolic –OH group of salicylic acid has become an ester group, and the –COOH group is unchanged. Aspirin therefore contains two functional groups from the families you know: a carboxylic acid (–COOH) and an ester (–COO–).

Making aspirin in the laboratory

Aspirin is made by reacting salicylic acid with ethanoic anhydride. This is an esterification, a preparation of an ester (LO 4.2.8), and it is an example of an organic compound used in a pharmaceutical product (LO 4.2.15). A few drops of concentrated phosphoric (or sulfuric) acid act as a catalyst, and the mixture is warmed gently (heated under reflux in some versions of the experiment, so that no vapour escapes). The –OH group of salicylic acid is converted to an ester, and ethanoic acid is the by-product.

Salicylic acid and ethanoic anhydride react in a 1:1 mole ratio, and aspirin is formed in a 1:1 ratio with the salicylic acid used. Water is then added to destroy any leftover ethanoic anhydride and to make the aspirin crystallise.

What aspirin does, and what happens to it in the body

Aspirin is an analgesic (it relieves pain), an antipyretic (it reduces fever) and an anti-inflammatory. In low doses it also makes blood less likely to clot, so it is used to reduce the risk of heart attack and stroke.

In the body, the ester group of aspirin is hydrolysed: it reacts with water to give salicylic acid and ethanoic acid.

Aspirin is therefore a modified form of salicylic acid. It passes through the mouth and stomach with the –OH group masked as an ester, and the active salicylic acid is released later, mainly in the blood and liver by enzymes (esterases).

Percentage yield

No reaction gives exactly the mass you calculate. The percentage yield compares what you actually get with the maximum possible:

The theoretical yield is the mass of product you would get if all the limiting reagent was converted.

A yield below $100\%$ has several possible causes:

• the reaction may not go to completion

• some product stays dissolved in the solution

• some product is left on the glassware or the filter paper

• side reactions take place

• some product is lost when the crystals are washed

Is the aspirin pure?

A drug must be pure. The crude aspirin from the reaction still contains impurities such as unreacted salicylic acid. Two things clean it up and check it: recrystallisation and melting point measurement.

Recrystallisation

1. Dissolve the crude solid in the minimum amount of hot solvent (such as an ethanol–water mixture).

2. Let the solution cool slowly. The aspirin is less soluble when cold, so pure crystals form.

3. The impurities are present in small amounts, so they stay dissolved in the cold solvent.

4. Filter the crystals with suction filtration, wash them with a little cold solvent and dry them.

Using too much solvent is the usual mistake. More of the aspirin stays dissolved and the yield drops.

Melting point as a test of purity

A pure solid melts sharply at one fixed temperature (pure aspirin melts at about $136\,^\circ\text{C}$). An impure solid melts below that temperature and over a wider range. The impurity particles disturb the regular crystal lattice, so it needs less energy to break down.

Testing for unreacted salicylic acid

Salicylic acid has a free phenolic –OH group. Aspirin does not, because that group has been turned into an ester. Add a few drops of iron(III) chloride solution to a solution of the sample:

• purple (violet) colour means salicylic acid is present

• no colour change (the solution stays yellow-orange from the iron(III) chloride) means no free phenol, so the aspirin is pure

Penicillin and antibiotic resistance

In 1928 Alexander Fleming noticed that a Penicillium mould growing on a culture dish had killed the bacteria around it. Later, Florey and Chain purified the active compound, penicillin, and it became the first widely used antibiotic.

An antibiotic is a substance that kills bacteria or stops them growing. Antibiotics do not work against viruses, so they will not help with a cold or flu.

How does penicillin work?

Bacteria are surrounded by a strong cell wall, which stops them bursting. Penicillin stops the bacteria building new cell wall. The bacteria cannot repair or grow their wall, so they burst and die. Human cells have no cell wall, only a cell membrane, so penicillin does not harm them. This is called selective toxicity.

Antibiotic resistance

Any bacterial population contains some individuals that, by chance, survive an antibiotic. If the course is stopped early, or the antibiotic is used when it is not needed, the weakest bacteria die and the most resistant survive. They multiply and pass on their resistance, so the population becomes mostly resistant. This is natural selection.

Strategies to slow resistance include:

• prescribing antibiotics only when they are needed

• finishing the full course

• better hygiene and vaccination, so there are fewer infections to treat

• restricting routine antibiotic use in farming

• research into new antibiotics

Taxol and the supply problem

Taxol (paclitaxel) is used in chemotherapy to treat cancers such as ovarian, breast and lung cancer. It was first isolated from the bark of the Pacific yew tree, and it stops cancer cells dividing.

The problem was supply. Removing the bark kills the tree, the trees grow slowly, and each tree gives only a small amount of drug. This is not sustainable: the species would be driven towards extinction long before enough drug was made.

Semi-synthesis

Chemists found a related compound in the needles of the European yew. The needles grow back, so the tree is not killed. This compound is a close relative of taxol. It is extracted and then converted to taxol in a few laboratory steps. A semi-synthesis starts from a natural compound with most of the structure already in place, and uses chemical reactions to finish the molecule. It solved the supply problem without destroying trees.

Ethical issues

Drug discovery from nature raises ethical questions:

• Do companies share profit with the countries and local communities whose traditional knowledge led to the discovery?

• Is it right to destroy a species to make a medicine?

• Will poorer patients be able to afford the finished drug?

Why modify natural products?

The drugs on this page follow the same pattern:

Why use a pure compound rather than a crude extract?

• The dose can be controlled, because a plant's content of the active compound varies with the season, soil and variety.

• Other compounds in the extract may be harmful or have unwanted side effects.

• A pure compound can be made in large amounts and tested properly in clinical trials.

Why modify the structure? The natural compound is often a starting point, not the finished drug. Chemists change the structure to:

• reduce side effects (salicylic acid to aspirin, which is gentler on the stomach)

• make the drug more effective or longer lasting

• make it easier or cheaper to make, or increase supply (taxol by semi-synthesis)

• change how it is absorbed or how it dissolves

Why biodiversity matters. Only a small fraction of plant, fungal and marine species have been tested for medical activity. Every species lost could take with it a molecule that might have cured a disease. Protecting rainforests, oceans and other ecosystems is also a way of protecting future medicines. A species that gives a drug also needs to be harvested sustainably.

Back to the start: willow bark gave us salicin and then salicylic acid. Chemists changed the –OH group to an ester to make aspirin, which is gentler on the stomach, can be made pure in a laboratory and can be dosed accurately. That change took a traditional remedy and made it a medicine.

Summary

• A natural product is a compound made by a living organism. Examples are salicin (willow bark), quinine (cinchona), morphine (opium poppy), penicillin (Penicillium mould) and taxol (yew).

• Aspirin (acetylsalicylic acid) has a carboxylic acid and an ester group. It is made from salicylic acid and ethanoic anhydride in a 1:1 mole ratio. It is used as an analgesic, antipyretic and anti-inflammatory, and in low doses to reduce blood clotting.

• Percentage yield $= \frac{\text{actual}}{\text{theoretical}} \times 100$. A yield below $100\%$ is caused by incomplete reaction, losses and side reactions.

• Purity is checked by melting point (impure means lower and broader) and by the iron(III) chloride test (purple means free phenol, so salicylic acid is present). Recrystallisation purifies the product.

• Penicillin inhibits bacterial cell wall synthesis and is harmless to human cells, which have no wall. Misusing antibiotics selects for resistant bacteria.

• Taxol was in short supply because it came from yew bark. Semi-synthesis from renewable yew needles solved the problem.

• Chemists use pure compounds and modify natural products to control dose, reduce side effects and improve supply. Biodiversity is a source of future drugs and raises ethical questions about fair use.