| Abstract |
Artemisinin is a novel sesquiterpene lactone with an endoperoxide function essential in the chemotherapy of chloroquine-resistant strains of Plasmodium falciparum malaria. Malaria parasites are known to utilize their host erythrocyte hemoglobin for their nutritional requirements. Heme moieties that are released as byproducts are extremely toxic for the parasite. Therefore one third of the heme is detoxified by polymerization into a crystalline , insoluble pigment named hemozoin. This pigment consists of a dense lattice of polymerized hemes. The heme component of intact malaria pigment obtained from in vitro cultures of P.falciparum, has been shown to be similar to those of hemin dimer and of β-hematin whose structure has been recently resolved. The remainder of the heme originating from hemoglobin degradation, appears to be degraded by a non-enzymatic process which leads to accumulation of iron in the parasite. Eventhough the mode of action of artemisinin is not clear, it is generally accepted by almost all workers in this field that the active species resulting from cleavage of peroxy bond of artemisinin are responsible for the parasiticidal activity. We have recorded FTIR spectra in the ν(O-O) and νas(Fe-O-Fe) regions of artemisinin and of hemin dimer that show the cleavage of the endoperoxide and that of the hemin dimer, respectively. We observed similar results in the trioxane alcohol/hemin dimer reaction. The RR spectrum of the artemisinin/hemin dimer and 18O-O18 trioxane alcohol/hemin dimer reaction revealed a mode assigned to the FeIV=O stretching vibration of a ferryl-oxo intermediate that occurs in the above mentioned reactions. Moreover, we investigated the decomposition products of artemisinin and trioxane alcohol with hemin. By monitoring the frequencies of the newly established lines the products of the reactions have been characterized. Τhe endoperoxide is degraded giving a mixture of a ring-contracted furano acetate and a hydroxydeoxy product. Similarly, the reduction of the peroxide bond by Fe(II) and Fe(III) was monitored. The use of 18O-O18 enriched trioxane alcohol has allowed us to identify several oxygen sensitive modes in the reaction with Fe(II) and Fe(III) and characterize the degradation products. A reaction mechanism has been proposed involving a C-C cleavage and a 1,5-H shift for the formation of the above mentioned products. The use of two mechanism-based trioxanes, synthesized by G. H. Posner provided an excellent opportunity to probe the importance of the 1,5-H shift pathway. The interaction of β-hematin with the above mentioned 1,2,4-trioxanes was also investigated. Our results do not indicate an extensive depolymerization of the synthetic pigment in contrast to the reported in vitro concentration-dependent depolymerization of hemozoin by artemisinin. The interaction of hemoglobin with artemisinin was also investigated. Our results demonstrate that Fourier transform infrared (FTIR) and resonance Raman (RR) spectroscopies are the appropriate tools to study the mode of action of antimalarial endoperoxides.
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Φασματοσκοπικές μελέτες της αρτεμισινίνης και των συνθετικών της παραγώγων με στόχο τη διευκρίνιση του μηχανισμού της ανθελονοσιακής δράσης τους
