The endoperoxides are a new class of antimalarial agents, ofwhich artemisinin (qinghaosu) is the prototype.We have previously shown that artemisinin is capable of alkylating proteins in model reactions. In the present study, we showed that when Plasmodium falciparum-infected erythrocytes are treated with a radiolabeled antimalarial endoperoxide, either arteether, dihydroartemisinin, or Ro 42-1611 (arteflene), the radioactivity is largely coverted into a form which can be extracted with sodium dodecyl sulfate (SDS). Autoradiograms of SDS-polyacrylamide gels showed that six malarial proteins are radioactively labeled by the three endoperoxides. This labeling occurs at physiological concentrations of drug and is not stage nor strain specific. The labeled proteins were not the most abundant proteins seen on Coomassie-stained gels. No proteins were labeled when uninfected erythrocytes were treated with these drugs, nor when infected erythrocytes were treated with the inactive analog deoxyarteether. Thus, the antimalarial endoperoxides appear to react with specific malarial proteins.
The multiexponential decay of tryptophan derivatives has previously been explained by the presence of rotamers having different fluorescence lifetimes, but it has been difficult to correlate rotamer structure and physical properties. New time-resolved and static data on dipeptides of the type Trp-X and X-Trp, where X is another aminoacyl residue, are consistent with the rotamer model and allow some correlations. That a dominant rotamer of Trp-X zwitterion has the -NH3+ group near the indole ring was inferred from absorption and fluorescence spectra, titrimetric determination of pKa values, photochemical hydrogen-deuterium-exchange experiments, decay-associated spectra, quantum yields, and decay kinetics. Analysis of the lifetime and quantum yield data for Trp dipeptides, especially X-Trp, suggests that static self-quenching is not uncommon. Highly quenched and weak components of the fluorescence do not contribute to the calculated mean lifetime, thus resulting in apparent static quenching. We propose the term quasi-static self-quenching (QSSQ) to distinguish this phenomenon from quenching due to ground-state formation of a dark complex. Mechanisms of quenching and the structure of statically quenched rotamers are discussed. The occurrence of QSSQ supports the idea that rotamers interconvert slowly. A major perceived deficiency of the rotamer model, namely, the apparent inability to predict reasonable rotamer populations from fluorescence decay data, may result from the presence of statically quenched species, which do not contribute to the fluorescence.
Synthesis of 12 beta-allyldeoxoartemisinin from dihydroartemisinin and subsequent transformations to other 12 beta-alkyldeoxoartemisinins are described. All compounds were tested in vitro versus two drug-resistant strains (Plasmodium falciparum) of malaria. The in vivo activity and toxicity of the most active compound, 12 beta-propyldeoxoartemisinin, were comparable to that of arteether.
A two-step reaction sequence between artemisinin and methanolic ammonia followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromatic amines for ammonia in the reaction sequence yields N-substituted 11-azaartemisinins in similar or greater yield. When Amberlyst 15 is replaced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45% and 15% yields, respectively. In vitro and in vivo test data for a number of novel N-substituted 11-azaartemisinins, against drug-resistant strains of Plasmodium falciparum, show they possess antimalarial activities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times more active in vitro and 4 times more active in vivo than artemisinin.
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