Reduction artemisinin

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

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-based regimens are often regarded as safe and effective drugs in the recent years however, clinically relevant artemisinin resistance has been reported both from laboratory and field studies. Some of these studies have shown that P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. This resistance was characterized by a slow parasite clearance in vivo, without corresponding reductions on conventional in vitro susceptibility testing.Although this resistance to artemisinin is still very mild and limited, its emergence would be disastrous because of the lack of alternative treatments. 

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. ... 

According to Coimbra et solvents play a central role in the majority of chemical and pharmaceutical industrial processes. The most used method to obtain artemisinin (1) from A. annua is through the use of organic solvents such as toluene, hexane, cyclohexane, ethanol, chloroform and petroleum ether. Rodrigues et al described a low-cost and industrial scaled procedure that enables artemisinin (1) enhanced yields by using inexpensive and easy steps. Serial extraction techniques allowed a reduction of 65% in solvent consumption. Moreover, the use of ethanol for compound extraction is safer when compared to other solvents. Flash column pre-purification employing silicon dioxide (Zeosil ) as stationary phase provided an enriched artemisinin (1) fraction that precipitated in hexane/ethyl acetate (85/15, v/v) solution. These results indicate the feasibility of producing artemisinin (1) at final cost lowered by almost threefold when compared to classical procedures. 

An artemisinin-fullerene hybrid 92, Fig. 7) was described by Jung et al Hybrid 92, inhibited by 50% angiogenesis processes at 5 nmol/egg, was were found to be more potent than malonate-linked dimer of artemisinin by itself (only 14% of reduction was observed). ... 

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. ... 

Iron(n) is known to decompose hydrogen and dialkyl peroxides to free radicals by reductive cleavage of the 0—0 bond and early investigations established the parasite s sensitivity to these species. When treated with radiolabelled C-artemisinin, the hemin-hemozoin fraction of the lysed malaria-infected erythrocytes was shown to contain a radiolabel, though the mechanism of incorporation is not clear. Meshnick and coworkers demonstrated that uninfected cells did not contain radiolabelled proteins whereas six radiolabelled proteins were isolated from cells infected with the Plasmodium falciparum (P. falciparum) strain of the parasite. It was suspected that one of the alkylated proteins was the Histidine Rich Protein (HRP) that was known to bind multiple heme monomers and therefore thought to be instrumental to the parasite s detoxification process. Moreover, iron chelators were found to inhibit the lethal effects of peroxides on the parasite. ... 

They concluded that the parasiticidal action of trioxanes involved reductive cleavage of the peroxide bond by intracellular iron-sulphur redox centres (rather than heme) and subsequent alkylation of the redox centre. This type of redox centre is known to exist in many enzymes and Wu and coworkers proposed that structural differences between those in the parasite and those in mammalian systems could account for the high selective cytotoxicity of artemisinin. 

Haynes and Vonwiller reported that artemisinin displayed multifarious reactivity in the presence of heme and non-heme iron(II) and also iron(III) °. The THF product 21 and artennuin D 13 were generally observed in varying ratios that were dependent upon the conditions used. Other products were also formed and the authors concluded that it was not possible to assign the parasiticidal species. However, they proposed an alternative mechanism of action that did not involve reductive ring opening of the peroxide bridge (Scheme 17). 

Fig. 1. Mechanism of action of artemisinin. By the reduction of the peroxide bridge two radical anions can be formed which will both lead to alkylation of proteins and parasite death. (From van Agtmael et al. Trends Pharmacol Sci 1999 20 199, reproduced with permission from Elsevier Science.)...

In another DFT study, the reductive decomposition of artemisinin 9a was investigated by the DFT B3LYP method, together with the 6-31G(d) and 6-31- -G(d,p) basis sets <2006BMC1546>. 

An FIPLC method using electrochemical detection in the reductive mode for the determination of artemether 28a and its metabolite dihydroartemisinin 29a <1997JCFI(B)145> and for the simultaneous quantification of artesunate 31 and dihydroartemisinin 29a in plasma has been developed <1997JCFI(B)259, 1998JCFI(B)201>. An effective reversed-phase FIPLC method using electrochemical and UV detection has been developed for the simultaneous determination in plant extracts of artemisinin and its bioprecursors such as arteannuin B 32a, and artemisitene 27 <1995JNP798, 2001JIC489>. 

The LiAlHa reduction of artemisinin 9a has been reported to result in complete reduction to compound 84 and partial reduction to the cyclic hemiacetal 85, along with two rearrangement products 86a and 86b <1986MI153, 1997T7493>. 

These values were compared with independent estimates of the °roor/ro ,ro values from thermochemical cycles, where data were available to evaluate them. In the case of di-cumyl peroxide, for example, the E° obtained experimentally differs from the result of a thermodynamic calculation by only 30 mV. It is of interest to note that the uncorrected a data would have led to °roor/rovro values only slightly negative to the corrected ones (0.06-0.07 V). The good agreement in these cases was used as the basis to support the use of the convolution approach to estimate °roor/rovro for systems where the necessary values for thermochemical estimates are not available. This has been particularly useful in the study of endoperoxides and was used to estimate the standard reduction potential of the antimalarial agent, artemisinin. ... 

The biosynthesis of artemisinin3 is of interest in that it provides clues to the chemical synthesis of artemisinin from its more abundant precursor in A. annua, artemisinic acid 2. Conjugate reduction of the acrylate double bond of 2 followed by singlet oxygenation leads,... 

The peroxide group is essential for neurotoxicity, and, depending on the assay, artemisinin could be considered relatively nontoxic or quite toxic. Removal of the oxygen atom at C-10 (10-deoxoartemisinin) resulted in a marked reduction in neurotoxicity. 

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