Endoperoxides artemisinin

Artemisia species have been used for many centuries to treat fevers and malaria, specifically cerebral malaria. They produce the sesquiter-penoid endoperoxide artemisinin (1), which accumulates in leaves and... 

The isolation and structural determination of the naturally occurring potent antimalar-ial sesquiterpene endoperoxides, artemisinin (qinghaosu) (6)28-31.439 recogni-... 

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

Studies on the mode of activity of the antimalarials related to artemisinin have centred on simpler 1,2,4-trioxanes, 1,2,4,5-tetraoxanes and bicyclic endoperoxides <00H(52)1345 00JCS(P1)1265 00JMC2753 00TL3145>. The chemical and electro-chemical reduction of artemisinin has been reported <00JCS(P1)4279>. 

Artemisinin ( qinghaosu ) (18), a sesquiterpene lactone antimalarial compound with an endoperoxide group, discovered in the Peoples Republic of China as a constituent of Artemisia annua L., has created great interest in the biomedical community, owing to its unique mechanism of action on the heme complex. Artemisinin serves as an option for the treatment of chloroquine (4l)-resistant malaria and is used in some Asian countries as an antimalarial. However, the use of artemisinin as a single agent anti-malarial is a potential risk since the malaria parasite may become resistant to this compound class. 

In 1972, Chinese researchers isolated, by extraction at low temperature from a plant, a crystalline compound that they named qinghaosu [the name artemisinin (la) is preferred by Chemical Abstracts, RN 63968-64-9]. The plant source of artemisinin is a herb, Artemisia annua (Sweet wormwood), and the fact that artemisinin is a stable, easily crystallizable compound renders the extraction and purification processes reasonably straightforward. The key pharmacophore of this natural product is the 1,2,4-trioxane unit (2) and, in particular, the endoperoxide bridge. Reduction of the peroxide bridge to an ether provides an analogue, deoxyartemisinin 3, that is devoid of antimalarial activity. ... 

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

Bicyclic endoperoxide antimalarials, such as arteflene (5) and naturally occurring ying-zhaosu A (7) and endoperoxide 8, share a unique feature of this class of compounds in their peroxide bond. As mentioned earlier, the peroxide bond of artemisinin has... 

The previous section dealt with the mechanisms behind the bioactivation of 1,2,4-trioxanes and endoperoxides. In this section we will examine briefly the suggested targets of the artemisinins. Since the original proposal by Meshnick and coworkers it is still believed by many researchers in the field that heme liberated from the haemoglobin proteolysis process is the species responsible for the bioactivation of the endoperoxide bridge to potentially toxic free radicals in the food vacuole of the parasite (see above). 

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 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. 

Woerdenbag and coworkers reported on the cytotoxicity of artemisinin endoperoxides to Ehrlich ascites tumour cells . Artemisinin had an IC50 of 29.8 p.M, whereas arteether, artemether, artelininc acid and sodium artesunate all had more potent activities, ranging from 12.2 to 19.9 p.M. It was found that opening of the lactone ring of artemisinin dramatically reduced the cytotoxicity. An ether dimer of dihydroartemisinin 106, prepared by... 

As described in this chapter, significant progress has been made in the elucidation of the chemical mechanisms of bioactivation and identification of potential biological targets of the antimalarial endoperoxide class of drug. Equally, medicinal chemists have had success in the preparation of both semi-synthetic artemisinin analogues and simplified... 

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. 

J.P. Begue, D. Bonnet-Delpon, The future of antimalarials Artemisinins and synthetic endoperoxides, Drugs Fut. 30 (2005) 509-518. 

Ab initio calculations using DFT have shown that the reactions which occur between artemisinin and some metal ions and complexes lead to a series of radicals which are probably responsible for its therapeutic activity. In particular, it has been shown that the interaction of Fe(ll) with artemisinin 9a causes the 0-0 bond to be broken, as do Fe(iii) and Cu(l), but not Zn(ll) <2004JST95>. DFT calculations have been carried out on the interactions of artemisinin and several other endoperoxides with the hexaaquaferrous ion [Fe(Fl20)6] and heme <2005JST87>. 

Calculations on the singlet and triplet states of artemisinin were carried out, using several levels of theory, in order to study its singlet-triplet excitations. It was concluded that FIF theory is not sufficient to estimate the adiabatic transition of this endoperoxide and that correlated calculations are required <1998JST87>. 

---