RESUMEN
Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.
Asunto(s)
Antimaláricos/síntesis química , Compuestos Ferrosos/química , Tetraoxanos/síntesis química , Animales , Antimaláricos/química , Antimaláricos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Espectroscopía de Resonancia por Spin del Electrón , Radicales Libres/química , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Plasmodium falciparum/efectos de los fármacos , Relación Estructura-Actividad , Tetraoxanos/química , Tetraoxanos/farmacologíaRESUMEN
3,5-Nonadiyne, in vitro, selectively inhibits endogenous nitric oxide release (IC(50)=6.7+/-0.8 microM) by rat peritoneal macrophages at doses that do not inhibit T cell proliferation. 3,5-Nonadiyne was isolated from root essential oil of Cachrys ferulacea (L.) CALESTANI, synonym Prangos ferulacea (L.) LINDLEY, obtained by hydrodistillation and spectrometricaly identified unambiguously.