SWITCHING FUNCTIONALITY: FROM NATURAL TOXINS TO DRUGS
Ancient discoveries frequently resulted from accidents. A nice example is the use of curare by Indian tribes in South America. The plant Chodondendron tomentosum and other plants of the rainforest were used to prepare an extract they called curare (the Indian word meaning poison). Arrow tips were submerged in the extract and used for hunting. The poison contained various components like d-tubocurarine. This compound blocks the signal transduction from nerves to skeletal muscles by binding to the receptor that usually reacts with the normal nerve transmitter acetylcholine. This inhibits the contraction of the muscle and the hunted animal can be caught. A high dose can even block the respiratory muscles of the animal and leads to its death. After that, the paralyzed prey can be safely consumed because the uptake of curare from the gastro-intestinal tract is limited and its excretion overwhelms the effect of the toxin.
d-Tubocurarine was used in treating muscle spasms and in anesthesia, if complete immobilization was needed during delicate surgery. Anesthetists have now new analogs of d-tubocurarine at their disposal that are safer to use.
The most common drug known by everyone is aspirin. This was in fact originally a trade name of the compound acetylsalicylic acid by the company Bayer AG. Aspirin became popular in the first half of the 20th century. The American patent held by Bayer expired in 1917, which led to a proliferation of aspirin products.
The idea of synthesizing acetylsalicylic acid came from the historic use of salicylic acid. This substance was originally obtained from the willow tree (Latin: salix). Salicylic acid was known easing pains and reducing fevers. For that reason the bark of the willow tree has been used for many centuries over the globe by Native Americans, Europeans, Chinese, ancient Greeks, and Egyptians.
The earlier mentioned ergot alkaloids from the ergot fungus contain lysergic acid. This compound has been used to synthesize LSD, the abbreviation of lysergic acid diethylamide in 1938. It has hallucinogenic properties and has been used by psychiatrists in the previous century to investigate schizophrenia. LSD is frequently indicated as “acid” and has been used extensively in the “flower power” period in the 1960s. Sometimes it was mixed through lemonade at parties through which ignorant partygoers were caught by strong visual “trips.” It has been visualized quite poignantly in Terry Gilliam’s Fear and Loathing in Las Vegas (Fig. 1.5).
Early pharmacists possessed a broad knowledge on botany. Many medications derived from plants and studies of the Materia Medica were a necessity. Seminal examples include plants like the Digitalis purpura, known as foxglove. The plant is regarded as extremely toxic because of the presence of digoxine. Administered in the right dose it is used as a drug in the treatment of heart failure. It increases the beating force of the heart. Moreover, it is used in the treatment of certain forms of irregular heart beat (atrium fibrillation) and still has a very important place in the pharmacotherapy in cardiology. This compound has a small therapeutic window, that is the difference between the concentration needed for an effect and the toxic concentration is very narrow. The blood plasma level should be between 0.8 and 2.0 ng/mL.
Many antitumor agents are derived from plants and used directly or chemically modified to enhance their activity and to sometimes lower their side effects. In a search for new cytostatics a screening program of plant extracts was initiated by the National Cancer Institute in the USA. It was found that the extract of Taxus brevifolia was active against several tumor cells. The isolated active compound from the extract mixture was paclitaxel which appeared to be active against ovarium carcinoma. From 2013 a
FIGURE 1.5 Visuals of a lysergic acid diethylamide trip experience.
semisynthetic method has been developed to make paclitaxel from Taxus baccata. Also plant cell fermentation processes have been employed using a Taxus cell line to make paclitaxel.
Doxorubicin is an anthracycline antibiotic with oncolytic (antitumor) activity. It is a very effective antitumor agent isolated from the bacteria Streptomyces peucetius. It inhibits the growth of rapidly dividing cells and it is widely used among others in the treatment of acute lymphatic leukemia and mamma and ovarium carcinoma. Doxorubicin has various long-term side effects that particularly manifest at higher dosages. Doxorubicin-induced heart toxicity has been investigated quite extensively because after surviving the cancer, the quality of life might be hampered by this toxicity. Many derivatives of doxorubicin have been synthesized over several decades, but it still plays a prominent role in oncology.
Many antibiotics are isolated from molds. Probably the most notable example is the discovery of penicillin by the Scottish scientist Alexander Fleming in 1928. He was working on staphylococci, bacteria, which can cause infections. On one of his Petri disks he discerned a mold, Penicillium notatum, and noticed that the staphylococci around that mold disappeared. It appeared that this mold was able to secrete a bacteria killing compound, which he called penicillin. Later research learned that the antibiotic blocks the building of the cellular membrane of bacteria. It started the era of antibiotics.
