The Discovery of Artemisinin

The earliest indication of qinghao as an antimalarial medication stems from a famous healer and alchemist, Ge Hong (284-346), during the Jin Dynasty (265-420 AD), who documented instructions to prepare extracts in his medical text Emergency Prescriptions Kept up one s Sleeve (Zhou hou beiji fang) (Fig. 5.189). [455] 

189 The Medical Treatments for 52 Diseases (on the left) were written on silk fabric and in part also on small bamboo strips. With its 9,950 characters, this is the most extensive medical text found in ancient Chinese tombs. -Ge Hong s 16th recipe In part Nr. 3 of his four-volume corpus Zhou hou be Jl fang (on the right) describes the preparation of extracts from qinghao to treat heat vexation and (intermittent) bone-steaming fevers (nue, Malaria). 

The actual active ingredient Qinghaosu ((+)-artemisinin) was as well isolated by Y. Tu in 1972. When in 1975 the structure of (+)-artemisinin was elucidated at the Chinese Academy of Sciences (CAS), Institute of Biophysics, by degradation reactions and crystal X-ray diffraction techniques, as published [458] in 1977, it became clear why the compound had a stability problem at elevated temperature. The peroxide ketal and the acetal moiety of this oxygen-rich sesquiterpene are easily cleaved under such conditions in aqueous media. 

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The discovery of artemisinin (Figure 8.16) by Chinese scienhsts in 1971 provided an excihng new natural product lead compound, and artemisinin is now used for the treatment of malaria in many countries. Its unusual endoper-oxide bridge is a key to its mechanism of achon, which involves complexation with haemin by coordination of the peroxide bridge with iron. This in turn interrupts the detoxi-hcahon process used by the parasite and generates free radical species which can attack proteins in the parasite. 

Recently, extensive efforts have been devoted to the synthesis of cycHc peroxides since the discovery of artemisinin and related antimalarial l,2,4-trioxanes. > As described previously, PET oxygenation is a unique but effective method for the preparion of cycHc peroxides, which is also appHcable to the synthesis of the peroxide structures from arylated cyclopropanes, aziridines, and olefins. - ... 

The pharmaceutical properties of artemisinin are far from optimal it is insoluble in water and only marginally soluble in oil. It has poor oral bioavailability and has been administered for the treatment of Plasmodium falciparum malaria in humans at total doses of about 1 g (over 3 days). Early studies by Chinese scientists in 1979 led to the discovery of dihydroartemisinin 3, artemether 4 (Artenam), and sodium artesunate 5, oil and water soluble derivatives, respectively (Figure 9.1 ).6-7 These drugs are currently in clinical use in Asia in a number of preparations such as suppositories, i.v. injectables, oil depos, to name only a few.8 Capsules containing 0.5 g of artemisinin for oral administration are available in Vietnam. 

The combined genomics and chemical approaches to plant terpenoid research are not restricted to the few plant species for which more or less complete genome sequences are now available. The discovery of many of the genes and enzymes for the formation of terpenoids such as menthol and related monoter-penes in peppermint Mentha x piperita) (15), artemisinin in Artemisia annua (16), Taxol in the yew tree (Taxus) (17), or conifer diterpene resin acids in species of spmce (Picea ) and pine (Pinus) (18) have been possible on the foundation of highly specialized efforts of EST and full-length cDNA sequencing combined with characterization of recombinant enzymes and analysis of the terpenoid metabolome of the target plant species. 

In the last two or three years we have assisted to a flowering of researches in the field of malaria, and in particular in the field of marine antimalarials. For example, the proposal of a new mechanism of action for artemisinin dates back only to 2003 and the discovery of the antimalarial potential of marine molecules as manzamines and plakortin is a result of the last two or three years. Thus, in conclusion, we are... 

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

Two major breakthroughs of the past few decades have renewed the assault of scientists to this infective disease. The first is the complete sequencing of the genome of Plasmodium falciparum [4] that is expected to provide useful information for the identification of new drug targets. The second is the discovery by Chinese researchers of artemisinin (qinghaosu), an endoperoxide sesquiterpene lactone, as the active principle of the sweet wormwood, Artemisia annua, an herbal remedy used in folk Chinese medicine for 2000 years [5]. This molecule and its... 

With over 250,000 species, the plant kingdom contains biodiversity which reflects known and novel compounds with potential therajjeutic activity (2,82,83). Furthermore, the World Health Organization has estimated that 80% of people in developing countries are dependent upon plant-centered traditional medicines for their primary health care (84). The examples of quinine and artemisinin cited above illustrate the proven utility of compounds from plants in the treatment of malaria. Moreover, it is likely that additional plant-derived antimalarial drugs await discovery since the literature indicates that in vivo or in vitro antimalarial activities have been identified in a broad and varied spectrum of botanical families (85-92). 

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