《天然药物化学》课程教学资源（教材）天然药物的研究与开发 Introduction to Natural Medicines R & D.pdf_大学文库

was regarded as punishment for one's sins.As a result,prayer and the hope for miracles were frequently the only methods available for the cure of disease.During the Renaissance,however,a renewed interest in the use of plant materials(usually herbs)sprang up in Europe.The first pharmacopoeia in the modern era,written by the German botanist Valerius Cordus (February 18.1515-September 25.1544),was published posthumously in 1546.(A pharmacopoeia is a list of drugs and medicines. with a description of the ilnesses for which they are useful and instructions for their preparation.) Valerius Cordus (Valeris Cors (Febuary 11515-Seplember 25,154)Gem erhals in history.He is also widely credited with developing a method for synthesizing ether(which h called by the poetic Latin name oleton dlci rimriofi,or "sweet oil of vitriol"). Cordus wrote prolifically,and identified and described several new plant species and vanetes he plant senus Cordia(紫草科破布木属)is named for him. Cordus's Dispensatorium was soon followed by other pharmacopoeia in other parts of Germany and other countries of Europe.The first such book in the United States,the Litit Pharmacopoeia,was published by Dr. William Brown in 1778 for use in military hospitals during the American Revolution. As in the modern world,plant materials were used not only to treat disease but also for other purposes,the most important of which was to produce hallucinogenic, psychedelic,or other"out-of-body"experiences.Many cultures throughout history have made the use of such materials an integral part of their religious ceremonies.For One of the most widely used of all illegal drugs is marijuana,which comes from the camnabis sativa plant.(Ted Kinsman/Photo Researchers,Inc.)example,ancient Hindu documents assert that the hallucinogenic effects of marijuana were fi rst discovered by the god Shiva,who ate leaves of the plant and found them very refreshing.Thereafter. the plant was routinely used in many Hindu ceremonies,usually in a form known as bhang.In the New World,the peyote cactus has been used in religious ceremonies for at least 10,000 years

was regarded as punishment for one’s sins. As a result, prayer and the hope for miracles were frequently the only methods available for the cure of disease. During the Renaissance, however, a renewed interest in the use of plant materials (usually herbs) sprang up in Europe. The first pharmacopoeia in the modern era, written by the German botanist Valerius Cordus (February 18, 1515 – September 25, 1544), was published posthumously in 1546. (A pharmacopoeia is a list of drugs and medicines, with a description of the illnesses for which they are useful and instructions for their preparation.) Valerius Cordus （Valerius Cordus (February 18, 1515 – September 25, 1544) was a German physician and botanist who authored one of the greatest pharmacopoeias and one of the most celebrated herbals in history. He is also widely credited with developing a method for synthesizing ether (which he called by the poetic Latin name oleum dulci vitrioli, or "sweet oil of vitriol"). Cordus wrote prolifically, and identified and described several new plant species and varieties. The plant genus Cordia （紫草科破布木属）is named for him. Cordus’s Dispensatorium was soon followed by other pharmacopoeia in other parts of Germany and other countries of Europe. The first such book in the United States, the Lititz Pharmacopoeia, was published by Dr. William Brown in 1778 for use in military hospitals during the American Revolution. As in the modern world, plant materials were used not only to treat disease but also for other purposes, the most important of which was to produce hallucinogenic, psychedelic, or other “out-of-body” experiences. Many cultures throughout history have made the use of such materials an integral part of their religious ceremonies. For One of the most widely used of all illegal drugs is marijuana, which comes from the cannabis sativa plant. (Ted Kinsman/Photo Researchers, Inc.) example, ancient Hindu documents assert that the hallucinogenic effects of marijuana were fi rst discovered by the god Shiva, who ate leaves of the plant and found them very refreshing. Thereafter, the plant was routinely used in many Hindu ceremonies, usually in a form known as bhang. In the New World, the peyote cactus has been used in religious ceremonies for at least 10,000 years

crystals,but had no idea as to its chemical composition.That limitation did not prevent morphine's being put to use as a drug,however.In 1826,Emanuel Merck (1794-1855),founder of the great Merck Chemical company,began producing pure morphine commercially for use as a drug Still,the compound's chemical structure remained a mystery for more than a century.Finally,in 195,the English chemist Sir Robert Robinson determined the structural formula for morphine(with the exception of one uncertain atom). Another historically significant example is the story of quinine.For centuries. quinine was the most effective drug for the treatment of malaria,which has long been one of the world's most serious and widespread infectious diseases.The substance was first used as an antimalarial treatment in the 1600s,although how it was discovered it still not known with certainty.In any case,its importance as a drug inspired the search for methods of extracting it from its natural source and determining its chemical structure so that it could be made synthetically The first problem was solved in 1820 when the French chemist Pierre-Joseph Pelletier (1788-1842)and his associate Joseph-Bienaime Caventou found a way to extract quinine from cinchona bark.That accomplishment gave no clue,however,as to the compound's chemical structure,so chemists were unable to synthesize quinine analogs in the laboratory.(In pharmacology,an analog is a drug whose chemical structure is similar to that of another drug,but whose chemical and biological properties may be quite different.) Indeed,it was not until the 1920s that progress was made in that direction.Then researchers discovered that a number of compounds belonging to the aminoquinoline family were effective in the treatment of malaria.Between the 1920s and the 1950s these two compounds were the most effective antimalarials available.Still,the search for the chemical structure of quinine itself went on,a pursuit that was not successful until 1944.In that year,the American research team of Robert Burns Woodward (1917-79)and William von Eggers (1917-)completed the monumental task of elucidating the structure of qunine.With this knowledge,it became possible for chemists to begin producing quinine synthetically in the laboratory and,more

crystals, but had no idea as to its chemical composition. That limitation did not prevent morphine’s being put to use as a drug, however. In 1826, Emanuel Merck (1794–1855), founder of the great Merck Chemical company, began producing pure morphine commercially for use as a drug. Still, the compound’s chemical structure remained a mystery for more than a century. Finally, in 1925, the English chemist Sir Robert Robinson determined the structural formula for morphine (with the exception of one uncertain atom). Another historically significant example is the story of quinine. For centuries, quinine was the most effective drug for the treatment of malaria, which has long been one of the world’s most serious and widespread infectious diseases. The substance was first used as an antimalarial treatment in the 1600s, although how it was discovered it still not known with certainty. In any case, its importance as a drug inspired the search for methods of extracting it from its natural source and determining its chemical structure so that it could be made synthetically. The first problem was solved in 1820 when the French chemist Pierre-Joseph Pelletier (1788–1842) and his associate Joseph-Bienaimé Caventou found a way to extract quinine from cinchona bark. That accomplishment gave no clue, however, as to the compound’s chemical structure, so chemists were unable to synthesize quinine analogs in the laboratory. (In pharmacology, an analog is a drug whose chemical structure is similar to that of another drug, but whose chemical and biological properties may be quite different.) Indeed, it was not until the 1920s that progress was made in that direction. Then researchers discovered that a number of compounds belonging to the aminoquinoline family were effective in the treatment of malaria. Between the 1920s and the 1950s, these two compounds were the most effective antimalarials available. Still, the search for the chemical structure of quinine itself went on, a pursuit that was not successful until 1944. In that year, the American research team of Robert Burns Woodward (1917–79) and William von Eggers (1917– ) completed the monumental task of elucidating the structure of quinine. With this knowledge, it became possible for chemists to begin producing quinine synthetically in the laboratory and, more

important,to develop analogs that were even more effective than the natural product. The most effective of the quinine analogs was mefloquine,developed during the Vietnam War as the result of a program developed by the Walter Reed Army Institute for Research to protect American soldiers against malaria. The morphine and quinine stories have established a model for the study of natural products that has been repeated many times in recent history,that is.the search for the chemical structure of a biologically active substance so that(1)the compound can then be made synthetically and (2)analogs of the drug can be produced and tested for biological activity.(The term biological refers to the benefi cial or adverse effects of a drug on living materials.)One of the most exciting achievements in this type of research involved the study of a natural product that has been used by Chinese herbalists for thousands of years to treat fever.Called qing hoa,it is also known as sweet wormwood,annual wormwood,and sweet annie.Its systematic name is Artemisia an.In addition to its use as an antipyretic(antifever medication),qing hoa has been used effectively as an antimalarial drug Beginning in the 1960s,the People's Republic of China initiated an aggressive program to discover the scientifi c basis for many traditional herbal remedies. including qing hoa As a result of that program,in 1972 Chinese scientists identifi ed the active ingredient in qing hao,a substance they called qinghaosu.Qinghaosu is also known as arteannuin in China and as artemisinine in the West.Artemisinine is a sesquiterpene,a class of naturally occurring compounds with the general formula C15H24.The sesquiterpenes are considered to be chemically derived from the basic compound,isoprene.Chinese researchers have developed a number of derivatives of artemisinine,including the compounds known as artemether,artesunate.arteether and artelinate,all highly effective in the prevention and treatment of malaria The structural formulas of artemisinine and its derivatives are shown in the following diagram.The formulas show the close structural relationship of the compounds.differing only in the shaded portion of the molecules

important, to develop analogs that were even more effective than the natural product. The most effective of the quinine analogs was mefloquine, developed during the Vietnam War as the result of a program developed by the Walter Reed Army Institute for Research to protect American soldiers against malaria. The morphine and quinine stories have established a model for the study of natural products that has been repeated many times in recent history, that is, the search for the chemical structure of a biologically active substance so that (1) the compound can then be made synthetically and (2) analogs of the drug can be produced and tested for biological activity. (The term biological activity refers to the benefi cial or adverse effects of a drug on living materials.) One of the most exciting achievements in this type of research involved the study of a natural product that has been used by Chinese herbalists for thousands of years to treat fever. Called qing hoa, it is also known as sweet wormwood, annual wormwood, and sweet annie. Its systematic name is Artemisia annua. In addition to its use as an antipyretic (antifever medication), qing hoa has been used effectively as an antimalarial drug. Beginning in the 1960s, the People’s Republic of China initiated an aggressive program to discover the scientifi c basis for many traditional herbal remedies, including qing hoa. As a result of that program, in 1972 Chinese scientists identifi ed the active ingredient in qing hao, a substance they called qinghaosu. Qinghaosu is also known as arteannuin in China and as artemisinine in the West. Artemisinine is a sesquiterpene, a class of naturally occurring compounds with the general formula C15H24. The sesquiterpenes are considered to be chemically derived from the basic compound, isoprene. Chinese researchers have developed a number of derivatives of artemisinine, including the compounds known as artemether, artesunate, arteether and artelinate, all highly effective in the prevention and treatment of malaria. The structural formulas of artemisinine and its derivatives are shown in the following diagram. The formulas show the close structural relationship of the compounds, differing only in the shaded portion of the molecules

The success in determining the chemical structure of qinghaosu is only one example of the accomplishments of chemists in attaining a better understanding of the relationship between the chemical structure of natural drugs and their pharmacological effects. Those accomplishments have formed the basis of a whole new phase of the pharmaceutical industry in which natural products and their derivatives provide an extensive source of new drugs. Microorganisms as the Source of Drugs Plants remained essentially the sole source of natural product drugs until well into the 20th century. Then in 1928 the discovery of penicillin by the Scottish bacteriologist Sir Alexander Fleming (1881–1955) opened an entirely new area of research in the field of Chemical formulas for artemisinine and its derivatives anti-infective drugs. Quite by accident, Fleming discovered that a sample of staphylococcus bacteria that he had inadvertently left out had begun to die out in certain areas of the culture. He determined that the change had come about in places where mold had fallen into the culture. Fleming isolated the mold and identifi ed it as Penicillium notatum. He inferred that the mold produced some chemical with the ability to attack and kill bacteria, a chemical that he later isolated and named penicillin. Penicillin was only the first of a new category of drugs that came to be called antibiotics (named by the Russian microbiologist Selman Waksman in 1941). Antibiotics were originally defined as chemical substances produced by microorganisms and able to inhibit the growth of or destroy bacteria and other microorganisms. It took more than a decade for the significance of Fleming’s discovery to be appreciated and for penicillin to be adopted by the medical profession as a treatment for infectious diseases. Once scientists turned that corner, however, they discovered a flood of new antibiotics in a relatively short period of time: streptomycin, by Waksman in 1943; bacitracin, by American bacteriologist Frank