Many of the earliest isolated pure compounds with biological activity were alkaloids. This was due to the ease of isolation. The nitrogen generally makes the compound basic and the compound exists in the plant as a salt. Thus, alkaloids are often extracted with water or mild acid and then recovered as crystalline material by treatment with base.

Prior to approximately 300 years ago, malaria was the scourge of Europe, likely having been introduced through the Middle East. Malaria is caused by protozoa of the genus Plasmodium, contained as spores in the gut of the Anopheles mosquitos, which then spreads the spores to humans when it bites. As the Spanish and Portugese explorers began to colonize South America, they discovered a cure for malaria known to the native Indians. This was the bark of the Cinchona trees. The use of Cinchona bark to treat malaria was first reported in Europe in 1633, and the first bark reached Rome about 12 years later. Teas made from the bark cured people suffering from malaria, one of the major scourges in Europe at the time, and the bark became known as Jesuit's bark. Because of the philosophical differences between Protestants and Catholics, many Protestants refused to be treated with the bark. One of the most prominent Protestants of the time, Oliver Cromwell, reportedly died of malaria because of this stubbornness.

Isolated originally from Cinchona succirubra, quinine is one of 31 alkaloids with related structures, and the principal antimalarial compound, in the plant. (Alkaloids have been defined in various ways, but one definition comes fairly close to actuality. An alkaloid is a plant-derived compound that is toxic or physiologically active, contains a nitrogen in a heterocyclic ring, is basic, has a complex structure, and is of limited distribution in the plant kingdom.) Malaria is still a major problem throughout the world, and, although synthetic antimalarial drugs largely supplanted quinine as the treatment for malaria during World War II, quinine is often once again the drug of choice as strains of malaria have become resistant to the synthetic drugs. However, the search for other antimalarial drugs from natural sources has also continued. One of the most promising new drugs is qinghaosu, isolated from Artemisia annua, a sesquiterpene (see below) which contains a unique trioxane structure.

Among the most famous of the alkaloids are the Solanaceae or tropane alkaloids. Plants containing these alkaloids have been used throughout recorded history as poisons, but many of the alkaloids do have valuable pharmaceutical properties. Atropine, the racemic form of hyoscyamine, comes from Atropa belladonna (deadly nightshade) and is used to dilate the pupils of the eye. Atropine is also a CNS stimulant and is used as a treatment for nerve gas poisoning. Scopolamine, another member of this class is used as a treatment for motion sickness. Cocaine, from Erythroxylum coca, is closely related in structure, is also a CNS stimulant, and has been used as a topical anesthetic in opthamology. It is also a drug of abuse. Cocaine was found in very small amounts in the original Coca-Cola formula, but was not the main concern of the USDA at the time. Caffeine was considered to be the major problem with the drink. Datura stramonium (Jimsonweed), a plant found in Virginia contains similar compounds.

The ergot alkaloids come from a fungus, Claviceps purpurea, which is a parasite on rye and wheat. The ergot alkaloids are responsible for ergotism (St. Anthony's fire), which manifests itself as gangrenous ergotism, resulting in loss of limbs, or convulsive ergotism, resulting in hallucinations. In both cases, death usually follows and outbreaks of ergotism caused 11,000 deaths in Russia as late as 1926. Today the problem is recognized and controlled. Some of the ergot alkaloids have been used to treat migraine headaches and sexual disorders in clinical applications. The most famous of these alkaloids is lysergic acid diethylamide, LSD, a powerful hallucinogen that is a synthetic derivative of the natural products. Similar alkaloids, particularly ergine, are also found in Mexican morning glories, such as Ipomeoa tricolor.

The morphine alkaloids, derived from the opium poppy, Papaver somniferum, are powerful pain relievers and narcotics. The narcotic activity of P. somniferum was noted on Sumerian tablets in 3500 B.C., making it one of the oldest drugs known. Opium is the dried latex of the seed heads of P. somniferum, and has been used as an analgesic (eliminates or relieves pain) and narcotic (induces sleep or drowsiness) in preparations such as laudanum and paregoric. Morphine is the principal alkaloid and was first isolated between 1803 and 1806. It was widely used for pain relief beginning in the 1830's, but was also recognized as being addictive. In an attempt to make morphine less addictive, Bayer chemists acetylated the hydroxyl groups to produce diacetylmorphine. This was marketed as a non-addictive pain reliever under the trade name Heroin for about two years in the early 1900’s, until it was recognized to be more addictive than morphine. Other derivatives of morphine have been developed and found use as opiate antagonists or as animal tranquilizers.

Vincristine, one of the most potent antileukemic drugs in use today, was isolated in a search for diabetes treatments from Vinca rosea (now Catharanthus roseus) in the 1950's along with vinblastine, a homologue in which the N-methyl group is oxidized to an aldehyde moiety. This is such a complex structure that it is still isolated from the plant (the Madagascan periwinkle) today rather than prepared by synthesis. The small change in structure, however, causes a significant change in pharmoacological efficacy. Vincristine (leurocristine, VCR) is most effective in treating childhood leukemias and non-Hodgkin’s lymphomas, where vinblastine (vincaleukoblastine, VLB) is used to treat Hodgkin’s disease.

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