RESUMO
New enantiomerically pure 1,2,4-trioxepanes 10a,b/11a,b were synthesized from D-glucose. Their conformational behavior was studied by low-temperature NMR and substantiated by DFT calculations. On evaluation of in vitro antimalarial activity, the adamantyl derivative 11b showed IC50 values in the low micromolar range, particularly against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 ± 0.12 µM).
Assuntos
Adamantano/síntese química , Adamantano/farmacologia , Antimaláricos/síntese química , Glucose/química , Oxepinas/síntese química , Adamantano/química , Antimaláricos/química , Antimaláricos/farmacologia , Cloroquina/farmacologia , Relação Dose-Resposta a Droga , Conformação Molecular , Estrutura Molecular , Oxepinas/química , Oxepinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Artemisinin derivatives, the current cornerstone of malaria treatment, possess also anti-angiogenic and anti-tumor activity. Hypoxia plays a crucial role both in severe malaria (as a consequence of the cytoadherence of infected erythrocytes to the microvasculature) and in cancer (due to the restricted blood supply in the growing tumor mass). However, the consequences of hypoxia onto the effects of artemisinins is under-researched. This study aimed at assessing how the inhibition of microvascular endothelial cell (HMEC-1) growth induced by dihydroartemisinin (DHA, an antimalarial drug and the active metabolite of currently in-use artemisinins) is affected by oxygen tension. Low doses of DHA (achieved in the patients' plasma when treating malaria) were more inhibitory in hypoxia, whereas high doses (required for anti-angiogenic or anti-tumor activity) were more effective in normoxia. The peroxide bridge is essential for cellular toxicity (deoxyDHA was inactive). High doses of DHA caused HMEC-1 apoptosis and G2 cell cycle arrest. Effects were mediated by the generation of oxidative stress as demonstrated by DCF-DA fluorescence and membrane lipid peroxidation analysis. Overall, these results suggest that DHA inhibition of endothelial cell growth is related to the level of tissue oxygenation and drug concentration. This should be considered when studying both the effects of artemisinin derivatives as antimalarials and the potential therapeutic applications of these drugs as anti-tumor agents.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Hipóxia Celular , Células Endoteliais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ácido Ascórbico/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Clinical treatment-failures to affordable drugs encouraged new investigation for discovery and development of new prophylactic and therapeutic interventions against malaria. The Drug Discovery Cluster (DDcl) of the Italian Malaria Network gathers several highly integrated and complementary laboratories from different Italian Institutions to identify, synthesise, screen in vitro and in vivo new antimalarial molecules directed against the intraerythrocytic stage of P. falciparum parasites and/or with transmission blocking activity to select lead compounds for further development. Complementary research activities, both in vitro and in the clinics, aim at investigating the pathogenetic mechanisms of severe malaria anaemia and the different manifestations of the disease in malaria-HIV co-infected patients to identify new therapies and improve survival.