Qinghaosu reactions

Liu H. J., Chew S. Y., Yeh W. L. Facile Selective Diels-Alder Reactions of Chiral 5,5-Dimethyl-4,6-Methano-2-Methoxycarbonyl-2-Cyclohexenone. Application to the Total Synthesis of Qinghaosu. Youji Huaxue 1993 13 314 321 Keywords (-)-/f-pinene, asymmetric synthesis... 

Study on the reactions of qinghaosu is heuristic, not only for determination of its structure, but also especially for understanding chemical properties and hence for the modification and utilization of the qinghaosu molecule to develop a new medicinal apphcation. Among them, reduction and acidic degradation have been paid the most attention and have received more practical application. 

Qinghaosu is a stable compound in comparison with common peroxides no decomposition is observed even at its melting point at 156-157 °C. However, pyrolysis takes place at 190 °C for 10 min, which provides a product mixture, from which compounds 108 (4%), 28 (12%), and 15 (10%) can be separated. " It is interesting that the latter two compounds are also the compositions of qinghao A. annua) the metabolites of qinghaosu in vivo, " and the reaction products of qinghaosu and ferrous ion vide infra) (Scheme 5-6). 

Another type of (9-glycosides (127), 12-(3 aryl ethers of dihydroartemisinin, was synthesized by a reaction of acetyl dihydroartemisinin or trifluoroacetyl dihydroartemisinin with various substituted phenols in the presence of trifluoroacetic acid. Most of these compounds were proved to have better antimalarial activity against P. berghei in mice than qinghaosu, but less activity than artemether. Unexpectedly,... 

Avery et al. have prepared a lot of 4- alkyl-, 4-(arylalkayl)-, and 4-(carboxyalkyl)-qinghaosu by their method with the reaction of vinylsilane and ozone as the... 

The Free Radical Reaction of Qinghaosu and Its Derivatives With Fe(II)... 

Since then, several qinghaosu derivatives have been treated with ferrous sulfate in the same reaction condition. Except for some hydrolysis products, similar derivatives of tetrahydrofuran compound 28 and 3-hydroxy deoxyqinghaosu 15 were... 

Posner et al. have synthesized the 3-methyl-derivatives of qinghaosu and found that the antimalarial activity of 3p-methyl derivative in vitro was about the same as qinghaosu however, the activity of the 3a-methyl- or 3,3-dimethy-derivative was at least two orders less than that of qinghaosu. This difference was supposed to come from the availability of the C-3 free radical for the later derivatives, but it was not mentioned whether these bio-inactive compounds were also inert in the reaction with ferrous ion. ... 

As mentioned, DNA could be cleaved with the Fenton reagent, and then we can take into consideration whether the qinghaosu-ferrous ion could also cleave DNA, although there are two different kinds of free radicals the oxygen radical from the Fenton reaction and the carbon free radical from the reaction of the qinghaosu-ferrous ion. It is makes sense that the malaria parasite is mainly living in the red blood cell however, the mature red blood cell has no nucleus, but the... 

Figure 5-6. Agarose gel illustrates the cleavage reactions of calf thymus DNA and salmon DNA hy qinghaosu or artemether and ferrous ion at 37 °C for 12 hours in a phosphate buffer...

Figure 5-8. Agarose gel illustrates the cleavage reactions of DNA pUC18 (40 ng/pL, lines 1-8) or calf thymus DNA (1 pg/pL, fines 10-17) by qinghaosu, catal)4ic amount of ferrous ion, and cysteine at 37 C for 12 hours. Lines 9 and 18 Mark DNA (pUC18 DNA +Hinf I, 65, 75, 214, 396, 517, 1419 BP from top sequentially).

As early as the 1980s, it was indicated that some proteins such as cytochrome oxidase in the membranes and mitochondria were a target for the action of qin-ghaosu. Meshnick et al. have performed a series of experiments about the interaction between qinghaosu and proteins in the presence of heme and have concluded that the binding between qinghaosu and albumin probably involves thiol and amino groups via both iron-dependent and -independent reactions. However, they have not isolated and confirmed such covalent adducts and have presented the ques-... 

Accordingly, as the first step, the interaction of qinghaosu and cysteine in the presence of a catalytic amount of Fe(lFlll) was studied. From the reaction mixture, a water-soluble compound was isolated. This compound could be visualized with ninhydrin on TLC, and it showed a formula of C16H27NO6S H2O. Treatment of this compound with acetic anhydride yielded a cyclic thioether 165, which in turn undoubtedly showed the formation of adduct 166 of 1 and cysteine through a a bond between C-3 and sulfur. A stable adduct 167 of cysteine and 170 was then isolated in 33% yield with the same reaction protocol. As mentioned, both adducts of cysteine with primary and secondary free radical derived from arte-mether were also identified recently, albeit in low yield (Structure 5-25). More... 

The successful identification of cysteine adducts encouraged us to study the reaction of 170 and GSH-cat Fe(III). After careful isolation, an adduct 174, similar to 167, was obtained in 1% yield from the aqueous layer, which was easily rearranged to compound 175 in acidic medium. Thereafter, a similar adduct 176 between GSH and the primary C-radical derived from qinghaosu was isolated and structurally confirmed by NMR and other spectroscopy (Stmcture 5-26). ... 

The actual active ingredient Qinghaosu ((+)-artemisinin) was as well isolated by Y. Tu in 1972. When in 1975 the structure of (+)-artemisinin was elucidated at the Chinese Academy of Sciences (CAS), Institute of Biophysics, by degradation reactions and crystal X-ray diffraction techniques, as published [458] in 1977, it became clear why the compound had a stability problem at elevated temperature. The peroxide ketal and the acetal moiety of this oxygen-rich sesquiterpene are easily cleaved under such conditions in aqueous media. 

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