Artemisin activity

Quinghaosu is the latest fundamental discovery in this area and is a heterocyclic compound that does not have a nitrogen atom in its structure. It is taken from a Chinese folk medicine. It is isolated from the plmt Artemisia annua. It is amazing that this compound, which is completely different than the other drugs described in this chapter in terms of structure, exhibits the exact same therapeutic effect. The main interest in quinoghaosu is based on the fact that it is active against resistant forms of malaria caused by P falciparum, and even its cerebral forms. Synonyms of this drug are artemisine, artemisinin, and others. 

In conclusion, the vast literature and its derivatives, particularly artesunate, artemether, and arteether, point out to the need to make these derivatives in quantities that would reduce their current production cost to make these drugs accessible to the economically underprivileged societies that are often the victims of malaria. A recent promising method in which artemisinic acid, a precursor to artemisinin, has been produced in engineered yeast. Therefore, microbially produced artemisinic acid holds promise to the syntheses of antimalarial drugs at affordable prices <2006N940>. Furthermore, anticancer activities of artemisinin 1 and its derivatives have been reviewed <2005MI995>. 

To search for stable, water-soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunate and artelinic acid, deoxoarteli-nic acid 134 was prepared (Scheme 5-18) and tested in vitro and in vivo. It was reported that 134 showed superior antimalarial activity and was more stable in simulated stomach acid than arteether. In 1992, Haynes et al. already reported on the synthesis of 5-carba-4-deoxoartesunic acid (135) from artemisinic acid (20) in a similar way, but they did not mention its activity at that time. ... 

A series of qinghaosu analogs of C-3 or/and C-13 modification were prepared from artemisinic acid by Lee et al. (Scheme 5-19). Among these analogs, only 13-nitromethyl qinghaosu had antimalarial activity comparable with qinghaosu. 

Jung et al. prepared 11-substituted deoxoartemisinin 136 from artemisinic acid (20) using photooxidation as the key step (Scheme 5-21). Compound 136 (R = CH2OH) was more active than qinghaosu and artesunate in vitro. 

Artemisia annua, known in China as Qinghaosu, contains artemisinin, which has antimalarial activity. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), arte-mether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisynthetic derivatives have been developed from dihydroartemisinin (11). The artemisinin derivatives are the subject of a separate monograph. 

ABSTRACT This article reviews the literature published in the last decade dealing with the transformation of a-santonin into bioactive or potentially bioactive sesquiterpenes. A number of syntheses starting from 8a-hydroxysantonin (artemisin) have also been included. Special emphasis has been placed on synthesized products that show biological activity. Major advances in this field include the application of new reagents and methodologies for the structural modification of the santonin skeleton and functionality, and its transformation into other sesquiterpenes, especially sesquiterpene lactones. 

Although the chemical stmcture of Artemisin has been established, total synthesis for labelling with C in the appropriate position requires at least 17 steps, some of which are unreliable and with very poor yield. By using Ba " C03 with a specific activity of 56 mCi/mM, we obtained by photosynthesis C-labelled Artemisin with a specific activity of 1.0 pCi/mg, which was sufficient to conduct the metabolic study. 

Up to 25 g artemisinic acid can be produced by the described approach. Since artemisinic acid is extracted from the fermentation broth and then chemically converted, the final product and active pharmaceutical ingredient is not a direct product from microbial fermentation. 

A spectacular example of the combination of an ene reductase with other enzymatic activities is about the cascade biosynthesis of artemisinin 43 (Scheme 3.11), natural drug possessing the most rapid action against Plasmodium fcdciparum (malaria). Artemisinic acid, precursor of 43, has been produced biotedmologically on g-scale by means of an engineered yeast [68]. Then, the C(11)=C(13) bond reduction of artemisinic aldehyde 44 was catalyzed by the cloned Dbrl (double bond reductase 1) protein from Artemisia annua to yield the (llS)-dihydroartemisinic aldehyde 45 precursor. It is interesting to note that the stereochemical outcome of this ene reductase is opposite to that observed for the reduction of the very similar substrate 23 with OYEs [69]. 

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