In artemisinin

Amorpha-4,11-diene synthase catalyses the first probable step in artemisinin biosynthesis. Phytochemistry 52 843-854. 

Chang YJ, Song SH, Park SH, Kim SU. (2000) Amorpha-4,11-diene synthase of Artemisia annua cDNA Isolation and bacterial expression of a terpene synthase involved in artemisinin biosynthesis. Arch Biochem Biophys 3S3 178-184. 

Woerdenbag et al also evaluated the influence of chiral center configurations present in artemisinin (1) structure on the proliferation of Ehrlich ascites tumor (ETA) cells. Compounds 11-hydroxyartemisinin (47) and 11-hydroxy-11-epi-artemisinin (48) (Fig. 4) were synthesized and the... 

Jung M, Lee K, Kim H, Park M. (2004) Recent advances in artemisinin and its derivatives and antimalarial and antitumor agents. Curr Med Chem 11 1265-1284. 

The action of the artemisinin derivatives is based on an unique mechanism. Haem or Fe in the parasite catalyzes the opening of the peroxide bridge in artemisinin, leading to the formation of free radicals which are lethal (see Fig. 1). 

The calculated nuclear quadrupole coupling constants (NQCCs) of in artemisinin 9a and some of its derivatives and the effects of charge density due to the nature of ligands on the NQCC of were described. All calculations were performed at the HF/3-21G level <2005MI366>. 

Artemisinin 1, a naturally occurring sesquiterpene peroxy-lactone, has been isolated in up to 0.25% yield from the dry leaves of Artemisia annua L.1 Interest in artemisinin is based on its phytomedicinal properties. In 168 b.c. China, as described in a Treatment of 52 Sicknesses, the leaves of A. annua (Qinghao) were used for the treatment of chills and fever.2 It was not until 1972 that the active antimalarial agent qinghaosu was isolated in pure form. This allowed for the unequivocal elucidation of its structure through the use of x-ray crystallography. This complex tetracyclic peroxide is now referred to as artemisinin in various sources such as Chemical Abstracts or the Merck Index. 

Another study calculated the quadrupole coupling constant (NQCC,x) of 170 in artemisinin and some of its derivatives. These calculations were made at the HF/3-21G level using the Gaussian 98 program. It was concluded that heme iron approaches the endoperoxide Oj position in preference to 02 <2005MI366>. 

There are two reasons for the great interest being shown in artemisinin and its derivatives. First, there is little cross resistance with Plasmodium falciparum between the members of this series and the quinoline-based antimalarials like chloroquine (203). On the contrary, significant potentiation of effect is observed in combination with chloroquine analogs such as mefloquine (204). Second, the high lipid solubility of, for example, arte-mether ensures rapid penetration into the CNS, so these sesquiterpene lactones are first-... 

Note In artemisinin series, conventional designation of stereochemistry is used (e. g., a is below the plane, while [) is above the plane), but the stereochemistry at C-10 is opposite to that used for glycosides.]... 

The subtle chemistry of difluoroenoxysilanes has not been fruitful in our search for new antimalarial drug candidates. All our attempts to convert ketones 21 into acids failed (Baeyer-Villiger reaction, oxidation of the aryl moiety). Furthermore, the configuration at C-9 in artemisinins is known to be crucial for the antimalarial activity [5], Ketones 21 are much less active in vitro and in vivo than artemether. 

Surprisingly, the allylic radical bromination of the nonfluorinated glycal 10 had not been reported, although the allyl bromide could obviously provide a shorter route to 16-substituted derivatives than the previously described approaches from artemisitene or artemisinic acid [28, 29, 59a, 65, 66], Conversely, reactivity of 10 toward electrophilic brominating agents was well documented. Dibromides [44,67] and bromohydrins [68,69] have been used for the introduction of ionizable functions in artemisinin at C-10 and C-9. 

Developments in artemisinin chemistry include the application of Heck coupling of lOP-allyldeoxoartemisinin to aryl iodides <05TL4243> and a Ru-catalysed self crossmetathesis reaction of artemisinin allylio ethers and alcohols which produces artemisinin dimers with high E/Z selectivity and without affecting the endoperoxide bridge <05OL5219>. 

In the last few years, variations on the basic stracmre have been launched in combination with other antimalarials (usually variations on the chloroquine structure) such as dihydroartemismin and piperaquine phosphate (Artekin), artemether and lumefantrine (Coartem), artesunate/mefloquine (Artequin) and artesunate, sulfamethoxypyrazine, and pyrimethamine (Co-Arinate). Currently, there is another fixed dose combination with an artemisinin derivative in clinical trials, pyronaridine/artesunate (Pyramax in Phase III). However, the tri-oxo scaffold system in artemisinins has led to the synthesis of not only artemisinin variations but to totally synthetic molecules with the trioxane moiety included, such as arterolane tosylate (81). This compound is in Phase II trials as a single agent under Ranbaxy and is in Phase I trials in combination with piperaquine phosphate, also under Ranbaxy. 

The peroxide bond in artemisinin (9) resists reduction with sodium borohydride, yielding a mixture of the epimeric lactols or dihydroartemisinins (65) <82MI 620-0l>. On the other hand, hydrogenation of (9) over Pd/CaCOs converts it into deoxyartemisinin (19), presumably by spontaneous dehydration of the intermediate diol (94) (Scheme 11) <88JMC645>. 

Interest in artemisinin continues and 9-substituted analogues <97TL6173> and 12-aryl derivatives <97H(45)1055> have been prepared from artemisinic acid. 

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