级 L.Panetal 24 roseus,also known as Vinca rosea (Madagascar based on natural products,12%"natural product and 12%synthetic d mainly to treat dif which the ph emodeled ugh they have efficiency against atural pro other forms of cancer. Those two anticancer agents act as mitotic inhibitors by binding to required to enhance therapeutic potency,to dimeric tubulin,and then leading to the failure increase bioavailability,to remove unpleasant of microtubule assembly in the metaphase stage side effects,and to help compensate for a short- [50-521. age in a natural product drug supply,or to derive different bioactivities.This section will focus on examples of semi-synthetic drugs of plant origin. Semi-synthetic Drugs Based on Plant A series of artemisinin-based semisynthetic Secondary Metabolites antimalarial derivatives.with all of them main- taining the key endoperoxide bridge,such as sm-ynthetic derivatives as dug arteether(18),artemether(19),artes unate (20) eloped from n ral duct lead and dihydr isinin(21),ha ninete to in nd the t ry and ed by dr gs like nl.Amo aspirin(acetyl id).From the 01 dihydroartemis sinin (artenimol), the potential of plant-de comp sidered as a common ac metabolite of leads in drug discovery has been realized on artemisinin derivatives [53,54].Currently numerous occasions [8].A survey released artemisinin-based therapies combined with recently revealed that over 40%of the new standard antimalarials such as amodiaquine. small-molecular single chemical entity drugs sulfadoxine-pyrimethamine,mefloquine,and introduced to the market from 1981 to 2006 lumefantrine are recommended by the World are natural product derivatives,with 28%of Health Organization(WHO)as first-line therapies them being chemical semi-synthetic modifications for malaria [55,56]. 18.R=Et arteether 19.R Me artemethe 20.R=3 COOH artesunate 21.R=H dihydroartemisinin
552 L. Pan et al. 24 roseus , also known as Vinca rosea (Madagascar periwinkle). Vinblastine and vincristine are used mainly to treat different forms of leukemia, although they have efficiency against several other forms of cancer. Those two anticancer agents act as mitotic inhibitors by binding to dimeric tubulin, and then leading to the failure of microtubule assembly in the metaphase stage [50– 52] . Semi-synthetic Drugs Based on Plant Secondary Metabolites The use of semi-synthetic derivatives as drugs developed from plant natural product lead compounds began at the end of the nineteenth century and may be exemplified by drugs like aspirin (acetyl salicylic acid). From then on, the potential of plant-derived compounds as leads in drug discovery has been realized on numerous occasions [8] . A survey released recently revealed that over 40% of the new small-molecular single chemical entity drugs introduced to the market from 1981 to 2006 are natural product derivatives, with 28% of them being chemical semi-synthetic modifications based on natural products, 12% “natural product mimics”, and 12% synthetic compounds in which the pharmacophore modeled was that of a natural product [20] . Synthetic optimization of the naturally occurring compounds is often required to enhance therapeutic potency, to increase bioavailability, to remove unpleasant side effects, and to help compensate for a shortage in a natural product drug supply, or to derive different bioactivities. This section will focus on examples of semi-synthetic drugs of plant origin. A series of artemisinin-based semisynthetic antimalarial derivatives, with all of them maintaining the key endoperoxide bridge, such as arteether ( 18 ), artemether ( 19 ), artesunate ( 20 ), and dihydroartemisinin ( 21 ), have been designed to improve the water solubility and the metabolic stability of artemisinin [53, 54] . Among them, dihydroartemisinin (artenimol), is considered as a common active metabolite of artemisinin derivatives [53, 54] . Currently, artemisinin-based therapies combined with standard antimalarials such as amodiaquine, sulfadoxine-pyrimethamine, mefloquine, and lumefantrine are recommended by the World Health Organization (WHO) as first-line therapies for malaria [55, 56] . O O O O OR 18. R = Et 19. R = Me 20. R = 21. R = H arteether artemether artesunate dihydroartemisinin H H O COOH
4 Pant-Derived 553 As mentioned before,the market demand of of this compound begins from(--shikimic the anticancer drug.paclitaxel(15,Taxol)was acid (25),which serves as the key intermediate threatened initially by an unsustainable natural in the biosynthesis of a variety of aromatic com- supply,which relied mainly on extracting this pounds in plants and microorganisms 121 compound from the bark of the slow-growing Shikimic acid was first isolated from the plant Pacific yew tree,from which it is produced only Illicium anisatum(Japanese"shikimi")in 1885. in a very low vield I571.Although the total syn- and is abundant in the star aniseed (Illicium thesis of paclitaxel has been described,this is verum)and the plant genus Liquidambar still inefficient when considered the extensive ("sweetgum)[65,66].In order to ov rcome the market need [5860].10-Deacetylbaccatin III shortage e of the natural so oure of shikimic acid (2).which is available high yicldiol fermentation of this substa the le 1as was intrd fully alterna as a sem tive method of cently, of paclitaxel by the major pharm al m synthetic metho phosphat ufacturer.Bristol-Myers Squibb (B-MS)[611.independent of shikimic acid has been devel Docetaxel(23),a related taxane anticancer drug oped [68]. can also prepared from 10-deacetylbaccatin III Nitisinone (26,OrfadinR)is the first drug (22)[62]. approved in Europe for the treatment of heredi- Oseltamivir phosphate (24,Tamiflu),a tary tyrosinemia type 1 (HT-1),a rare genetic neuraminidase inhibitor,is administered orally metabolic disorder caused by a deficiency of for the treatment and prevention of influenza A fumarylacetoacetatehydrolase(FAH),anenzyme and B virus infections,and stockpiling of this involved in the metabolism of tyrosine 69]. drug has been proposed to counter the threat of a Nitisinone is a derivative of leptospermone (27). pandemic such as avian flu 63.641.One synthesis an effective herbicide present in the bottlebrush HO H HO HO 22.10-deacetylbaccatin III 23.docetaxel 4.osetamivir phosphat 25.()-shikimic acid 26.nitisinone
24 Plant-Derived Natural Products as Leads for Drug Discovery 553 As mentioned before, the market demand of the anticancer drug, paclitaxel ( 15 , Taxol®) was threatened initially by an unsustainable natural supply, which relied mainly on extracting this compound from the bark of the slow-growing Pacific yew tree, from which it is produced only in a very low yield [57] . Although the total synthesis of paclitaxel has been described, this is still inefficient when considered the extensive market need [58– 60] . 10-Deacetylbaccatin III ( 22 ), which is available with a relatively high yield from the leaves of other renewable yew species, such as Taxus baccata L., was introduced as a semi-synthetic precursor compound of paclitaxel by the major pharmaceutical manufacturer, Bristol-Myers Squibb (B-MS) [61] . Docetaxel ( 23 ), a related taxane anticancer drug can also prepared from 10-deacetylbaccatin III ( 22 ) [62] . Oseltamivir phosphate ( 24 , Tamiflu®), a neuraminidase inhibitor, is administered orally for the treatment and prevention of influenza A and B virus infections, and stockpiling of this drug has been proposed to counter the threat of a pandemic such as avian flu [63, 64] . One synthesis of this compound begins from (−)-shikimic acid ( 25 ), which serves as the key intermediate in the biosynthesis of a variety of aromatic compounds in plants and microorganisms [2] . Shikimic acid was first isolated from the plant Illicium anisatum (Japanese “shikimi”) in 1885, and is abundant in the star aniseed ( Illicium verum ) and the plant genus Liquidambar (“sweetgum”) [65, 66] . In order to overcome the shortage of the natural source of shikimic acid, fermentation of this substance by metabolically engineered Escherichia coli strains has been developed successfully as an efficient alternative method of production [67] . Recently, a total synthetic method for oseltamivir phosphate independent of shikimic acid has been developed [68] . Nitisinone ( 26 , Orfadin®) is the first drug approved in Europe for the treatment of hereditary tyrosinemia type 1 (HT-1), a rare genetic metabolic disorder caused by a deficiency of fumarylacetoacetate hydrolase (FAH), an enzyme involved in the metabolism of tyrosine [69] . Nitisinone is a derivative of leptospermone ( 27 ), an effective herbicide present in the bottlebrush 23. docetaxel HO O O O O HO OH AcO O H N H O O OH O 22. 10-deacetylbaccatin III HO HO O O O HO OH AcO O H O NH2.H3PO4 F3C NO2 HN O O O HO COOH HO OH 24. oseltamivir phosphate 25. (-)-shikimic acid O O O O O O O 26. nitisinone 27. leptospermone