Artemisinin chemistry

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>. 

Chemistry and biological activity of artemisinin (sesquiterpene y-lactone with oxepane fragment and transannular peroxide bridge) and related antimalari-als 99H(51)1681. 

Ryd6n A-M, Kayser O (2007) Chemistry, biosynthesis and biological activity of artemisinin and related natm-al peroxides. 9 1-31... 

Chemistry, Biosynthesis and Biological Activity of Artemisinin and Related Natural Peroxides A.-M. Ryden O. Kayser... 

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 total synthesis of artemisinin via conventional chemistry has also been achieved. In 1983, Schmid and Hofheinz pubhshed a paper showing the complete synthesis of artemisinin from (-)-Isopulegol (Scheme 10), with 5% overall yield. Since then, several other total synthesis of arteminisin... 

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. 

The following section will highUght the chemistry that has been carried out on the artemisinin framework in pursuit of analogues with improved pharmacological profiles. 

Table 1 summarizes the synthetic and antimalarial profiles of selected endoperoxides. Clearly, synthetic organic chemistry has enabled several excellent potential drng candidates to be prepared, some of which have outstanding antimalarial properties. At the forefront of these efforts are the trioxolanes prepared by Vennerstrom and colleagnes. The challenge in this field in future years will be to construct additional endoperoxide templates that can be prepared in a few steps using scalable synthesis and have similar pharmacological profiles to lead semi-synthetic artemisinins and trioxolanes (e.g. 6). 

As in more recent years, the chemistry of seven-membered ring systems has been dominated by the chemistry of oxygen heterocycles in the form of the marine toxins and, to a lesser extent, the antimalarial artemisinin. Indeed, if it were not for the interest in these systems it would have been a sparse year indeed. For this reason the division of this report will be into just three section, nitrogen, oxygen, and other systems. 

In addition to the CIEEL mechanism, peroxides and endoperoxides are key intermediates in a number of chemical and biological processes. There are a growing number of examples where ET to the 0-0 bond in these systems is accepted as an important step in their activity. For example, it is now generally agreed that the first step in the bioactivity of the recently discovered potent antimalarial, artemisinin, involves an ET from Fe-heme to the 0-0 bond, leading to fragmentation and a number of psytotoxic radical intermediates. " In contrast to the enormous amount of literature on the thermal and photochemical reactivity of peroxides, there is relatively little known about their ET chemistry. It is this lack of kinetic data on ET to peroxides and endoperoxides and the possible relationship of this data to Saveant s model for dissociative ET that initiated our own interest in this chemistry.22 23 2 - - - ... 

This chapter comprises an update on the chemistry of 1,2-dioxepines, 1,2-oxathiepines, and 1,2-dithiepines which appeared in Chapter 9.10 in CHEC-II(1996). It is evident that the structural nature, in terms of construction and/or stability of each of these seven-membered heterorings, which include a relatively weak O-O, O-S, or S-S bond, lies behind the paucity of publications in this area. However, the literature on the effective antimalarial artemisinin 1, a remarkably stable endoperoxide, and especially its derivatives more than make up for this deficiency. 

Bhattacharya AK and Sharma RP (1999) Recent developments on the chemistry and biological activity of artemisinin and related antimalarials - an update. 

Vroman, J. A. Mehrotra, S. Avery, M. A. Miller, R. Three Synthetic Routes to 9-Butyl Artemisinin. 22nd Annual MALTO Medicinal Chemistry-Pharmacognosy Meeting, Xavier University, New Orleans, LA, 1995. 

Li Y, Huang H, Wu YL. Qinghaosu (Artemisinin) - A fantastic antimalarial drug from a traditional Chinese medicine. In Medicinal Chemistry of Bioactive Natural Products. Liang XT, Fang WS, eds. 2006. John Wiley Sons, Hoboken, NJ, pp. 183—256. Meshnick SR. In Antimalarial Chemotherapy. Rosenthal PI, ed. 2001. Humana Press, Totowa, NJ, pp. 191-201. 

Haynes RK. From artemisinin to new artemisinin antimalarials Biosynthesis, extraction, old and new derivatives, stereochemistry and medicinal chemistry requirements. Curr. Top. Med. Chem. 2006 6 509-537. 

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