## The most well-known secondary metabolites

Morphine, a substance found in poppy heads and the fruits of the opium poppy (Papaver somniferum), was first discovered in 1804 and is named after the Greek god of dreams, Morpheus. It was the first purely plant-based product commercially produced and sold in 1826. Due to its ability to relieve pain, morphine is mainly used for the management of chronic pain and as part of pre-operative preparations for patients. However, tolerance to the drug can develop with regular use, necessitating an increase in dosage. Other opioids, such as codeine and heroin, can also be produced chemically from morphine. Another well-known plant is deadly nightshade (Atropa belladonna), whose extract was often sought by women in the Middle Ages. This is because it is a powerful antispasmodic, which means it relaxes muscles, and one of its effects is mydriasis – excessive dilation of the pupils, which was considered very attractive in the Middle Ages. To this end, it is also named Belladonna, translated from Italian for “beautiful women”, but a more sinister side to the plant is that the berries are thought to be the poison that made Juliet appear dead in Shakespear’s Romeo and Juliet. Another well-known secondary metabolite from the deadly nightshade is atropine, which has hallucinogenic effects and can be a powerful poison, as with most herbal remedies, if misused. It is currently used to treat digestive problems and in ophthalmology, as it facilitates patient examination. Foxglove (Digitalis purpurea) was very popular among herbalists and folk healers who used it to treat heart disease. However, this treatment was gradually abandoned because it was very difficult to determine the precise dosage of the herb. The secondary metabolite, digitalin, is still used as a medical treatment to increase heart contractions and regulate heart rate.

The plant that helped win the Nobel Prize in Physiology or Medicine in 2015, Artemisia annua, commonly known as sweet wormwood, is often used as a medicine for digestive problems. But what makes this plant exceptional? We must go back to the Vietnam War to find the answer to this question. The problem during this period, as well as the war conflict, was the spread of malaria. The situation was so severe that representatives from China and Vietnam met and jointly created a military project called 523, which focused on developing new antimalarial drugs. The project also included chemist Tu Youyou, who studied traditional Chinese medicine texts and, with the help of the 523 project, isolated the substance artemisinin (qinghaosu) from sweet wormwood, a new antimalarial drug. Malaria is caused by the parasitic organism Plasmodium falciparum, transmitted by mosquitoes of the genus Anopheles. It all starts when a mosquito bites a patient with malaria. In the mosquito's gut, the infected blood with parasite male and female gametocytes undergo sexual reproduction, and the parasite passes through several developmental stages. The final infectious stage (sporozoites) migrates to the mosquito's salivary glands. The mosquito then transmits these sporozoites into the bloodstream of a new host, where they reach the liver and undergo a non-sexual life cycle. After 6-12 days, infected liver cells rupture, releasing the parasite (merozoites) into the bloodstream. Plasmodium then attacks red blood cells, reproducing intensively until the cells rupture. This phase is often associated with malaria attacks and fever, as the destruction of many red blood cells and the release of their contents into the bloodstream is toxic to humans. Later, this merozoite form differentiates into sexual cells (gametocytes), and the cycle repeats. Artemisinin can block the proteins of the Plasmodium parasite, preventing them from functioning correctly in the phase of attacking red blood cells (see Figure 11.3).

A clinically relevant chemotherapy drug is the metabolite of the western yew tree (Taxus brevifolia) called paclitaxel. It is mainly used in the fight against cancer due to its ability to affect cell division by preventing the shortening of tubulin (a component of the cell cytoskeleton) and thereby halting the cell in a specific phase of division. This way, paclitaxel prevents cancer cells from intense and continuous division and damaging the body. Another metabolite that can be used in various fields of research and medicine is colchicine, a substance isolated from the autumn crocus (Colchicum autumnale). Colchicine can block the formation of microtubules and disrupt the process of mitosis (consequently, it is classified as a mitotic poison). Interestingly colchicine is also used in plant breeding because it can induce polyploidy (duplication of the entire set of chromosomes). By preventing a cell from dividing, the genetic information doubles, which is passed on to the next generation as a polyploid. Compared to humans, who are diploids (two alleles of the same gene), some plants can have many times more sets of chromosomes (for example wheat has six copies of chromosomes). Since colchicine also has anti-inflammatory effects, it is used in medicine to treat gout. During the COVID-19 pandemic, scientists again turned to medicinal plants and using them as sources of new bioactive compounds that could potentially treat this disease. Since many plant metabolites (such as quercetin, colchicine, and emodin) have antiviral or anti-inflammatory effects, they represent potential candidates in the fight against the SARS-CoV-2 virus.