Artemisinin derivatives

Titanium tetrachloride-catalysed Michael additions of trimethylsilyl enol ethers to artemisitene afforded a neat route to 14-substituted artemisinin derivatives of type 125 (eg. R = allyl) and to 9-epiartemisinin derivatives 126 some of these compounds were more active against Plasmodium falciparum than artemisinin <00BMCL1601>. A series of 11-azaartemisinins also have better activity than artemisinin <00BMC1111>. On the other hand, epiartemisinin, prepared by base-catalysed epimerisation of artemisinin, has been shown to have poor antimalarial activity <00HCA1239>. 

Many seven-membered ring heterocyclic derivatives show pharmacological activity, and many, for example the benzodiazepines, nevirapine (anti-HIV), trineptine (antidepressant) and artemisinin derivatives (anti-malarial) are used clinically. The number of papers reporting pharmacological activity of new compounds or pharmacological mode of action studies continues at a significant rate. 

Artemisinic acid can indeed be easily converted to artimisinin using conventional chemistry in three steps via reduction of the exocyclic methylene group and photooxidation of the resulting dihydroartemisinic acid, with 30% overall yield (see Scheme 9) Other artemisinin derivatives have also been prepared using artemisinic acid as the starting material. ... 

The large diversity of biological activities including antimalarial, antioxoplasmosis, antileishmaniasis, antishistosomiasis, antitrypanosomiasis, antiviral, antifugal and even anticancer activities displayed by artemisinin and artemisinin derivatives (cf. Ref. 55 for a review) added to the multitude of artemisinin-inspired trioxanes, trioxolanes, tetraoxa-cycloalkanes and peroxide, homodimeric-, trimeric- and even tetrameric artemisinin derivatives recently designed and synthesized is a clear indication that in the future, these compounds will become even more important in the chemotherapy of various diseases, perhaps even above and beyond those mentioned here. 

Price R, Van Vugt M, Phaipun F, Fuxemburger C, Simpson J, McGready R, Kuile FT, Khan A, Chongsuphajasiddhi T, White NJ, Nosten F. (1999) Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 60 547-555. 

Nontprasert A, Pukrittayakamee S, Dondorp AM, Clemens R, Looareesuwan S, White NJ. (2002) Neuropathologic toxicity of artemisinin derivatives in a mouse model. Am J Trop Med Hyg 67 423 29. 

Ekthawatchai S, Kamchonwongpaisan S, Kongsaeree P, Tamchompo B, Thebtaranonth Y, Yuthavong Y. (2001) C-16 artemisinin derivatives and their antimalarial and cytotoxic activities Synthesis of artemisinin monomers, dimers, trimers and tetramers by nucleophilic additions to artemisitene. JMed Chem 44 4688 695. 

The antiproliferative structure-activity relationships of 96 artemisinin derivatives are also discussed. 

FDA) for use in humans to treat malaria because this drug is considered a safe drug with few side effects.These features prompted various scientists around the world to evaluate the potential of artemisinin (1) and derivatives to control cancer cells proliferation. This chapter reviews the recent advances on analytical methods for extraction and quantification of artemisinin (1) from A. annua. Examples of artemisinin-derivatives with antiproliferative activities are listed, describing the structure-activity relationships of 96 compounds. This knowledge is essential for future development and use of artemisinin derivatives in cancer therapy. The mechanism of action of artemisinin and derivatives on cancer cells have been well reviewed in literature and therefore is not discussed in this chapter. 

Liu Y, Wong VKW, Ko BCB, Wong MK, Che CM. (2005) Synthesis and cytotoxicity of studies of artemisinin derivatives containing lipophilic alkyl carbon chains. Org Lett 7 1561-1564. 

Beekman AC, Barentsen ARW, Woerdenbag HJ, Uden WV, Pras N, Konings AWT, El-Feraly FS, Galal AM, Wikstrom HV. (1997) Stereochemistry-dependent cytotoxicity of some artemisinin derivatives. JNat Prod 60 325-330. 

Posner GH, McRiner AJ, Paik IH, Sur S, Borsmik K, Xie S, Shapiro TA, Alagbala A, Foster B. (2004) Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. J Med Chem 47 1299-1301. 

As has been discussed, the artemisinin class of antimalarials exerts their effect by iron-mediated cleavage of the endoperoxide bridge and subsequent formation of free radicals. Recent studies have reported on the cytotoxic activity of artemisinin derivatives against tumour cells. The iron content of tumour cells is generally higher than that of normal cells, and since ferrous iron is required for the bioactivation of artemisinin this provides a strategy for the use of artemisinins against tumour cells. 

G3 factor, 199, 201, 202 mechanisms, 1309, 1310 NMR spectroscopy, 710 OZ 277 drug candidate, 1317, 1319, 1331 Plasmodium falciparum resistance, 608 synthetic, 1282, 1317-31 antimalarial activities, 1332 semi-synthetic artemisinin derivatives, 1313-17, 1332... 

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). 

Fig. 2. Structure of artemisinin derivatives. (From van Agtmael et al. Trends Pharmacol Sci 1999 20 202, reproduced with permission from Elsevier Science.)...

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

Artemisinin is a natural endoperoxide-containing sesquiterpene, isolated from a plant used in traditional Chinese medicine. Acetalic artemisinin derivatives (arte-mether, artesunate) are very active against chemo-resistant forms of Plasmodium falciparum, and are clinically used for the treatment. However, they suffer from an unfavourable pharmacological profile. They are quickly metabolised by fast oxidative metabolism, hydrolytic cleavage and glucuronidation. 

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