Artemisinin and derivatives

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. 

Initially, we sought a practical total synthesis of the natural enantiomer (+)-artemisinin (1) to support clinical therapeutic studies with artemisinin and derived prodrug congeners, such as artemether and artesunate, and by providing a radiolabeled version of artemisinin for metabolism and mode of action studies (Eq. 1). Associated model studies from our total synthesis resulted in numerous additional analogues for our fledgling SAR study and the conception of other structural... 

Haynes, R. K. Artemisinin and derivatives The future for malaria treatment Curr. Opin. Infect. Dis., 2001, 14 719-726. 

Haynes, R. K. Artemisinin and derivatives—the future for malaria treatment. Curr. Opin. Infect. Dis., 2001, 14(6) 719-726 Haynes, R. K. Ho, W.-Y. Tsang, H. W. Abstract of The Third International Symposium for Chinese Medicinal Chemists, Hong Kong, Dec. 28-31, 2002, 13. 

Fig. 1. Artemisinin and derivatives (training set) with different degrees of cytotoxicities against human hepatocellular carcinoma FfepG2...

Fig. 2. Plot of PC1-PC2 scores for artemisinin and derivates (training set) with activity against human hepatocellular carcinoma HepG2. More active compounds displayed on the left side (plus sign) while less active ones on the right side (minus sign)...

Rodriguez Romero, M. Serrano Garcia, M. A. Vallejo, M. Efferth, T. A. Garcia Marin, J. J. Use of artemisinin and derivatives in the preparation of drugs such as antiviral agents. Span. ES 2245248, 2005 Chem. Abstr. 2006,145, 321850. 

Interaction of biomolecules with ginghaosu (artemisinin) and its derivatives in the presence of Fe(II) ion—an exploration of antimalarial mechanism 99PAC1139. 

Artemisinin and its derivatives, artesunate and arthemether, kill both asexual and sexual blood stages (Fig. 2). However, artemisinins are quickly eliminated from the body, resulting in parasite recrudescence, and are therefore combined with schizontocides that have a longer biological half-life, such as amodiaquine,... 

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. 

It is clear that no other compound or family of compounds have affected the chemotherapy of malaria as much as quinine and its derivatives, and artemisinin and its derivatives. Nevertheless, there are some classes of natural products that have made it to the market or at least at the advanced stage of clinical trials as antimalarial. Among them are quinones, chalcones and xanthones. 

Hencken CP, Kalinda AS, D Angelo JG. (2009) The anti-infective and anti-cancer properties of artemisinin and its derivatives in JE Macor (ed.). Annual Reports In Medicinal Chemistry, Vol 44 Academic Press, pp. 359-378. 

Ribeiro IR, Olliaro P. (1998) Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Med Trop 58 50-53. 

Artemisinin, a tetracyclic 1,2,4-trioxane isolated from Artemisia annua L., is currently recommended as a first-line agent against Plasmodium falciparum malaria. Artemisinin and its synthetic derivatives have also been shown to be promising prototypes for the development of new antiproliferative agents. This chapter presents the recent advances on the analytic methods for extraction and quantification of artemisinin from A. annua plants as well as the biological properties of this natural product. 

Fig. 6. Chemical structure of artemisinin (l)-derived trimers and tetramers.

Chaturvedi D, Goswami A, Saikia PP, Barua NC, Rao PG. (2010) Artemisinin and its derivatives A novel class of anti-malarial and anti-cancer agents. Chem Soc Rev 39 435 54. 

Efferth T. (2006) Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets 7 407 21. 

Firestone GL, Sundar SN. (2009) Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev Mol Med 11 1-15. 

Hon J, Wang D, Zhang R, Wang H. (2008) Experimental therapy of hepatoma with artemisinin and its derivatives In vitro an in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res 14 5519-5530. 

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