RESUMEN
Greater than the sum of its parts: Artemisinins are currently in phaseâ I-II clinical trials against breast, colorectal and non-small-cell lung cancers. In an attempt to offer increased specificity, a series of hybrid artemisinin-polypyrrole minor groove binder conjugates are described. DNA binding/modelling studies and preliminary biological evaluation give insights into their mechanism of action and the potential of this strategy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/síntesis química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Artemisininas/farmacología , ADN/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Polímeros/farmacología , Pirroles/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/química , Artemisininas/química , Sitios de Unión/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ADN/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Células HT29 , Humanos , Modelos Moleculares , Conformación Molecular , Simulación de Dinámica Molecular , Pruebas de Sensibilidad Parasitaria , Polímeros/química , Pirroles/química , Relación Estructura-Actividad , TermodinámicaRESUMEN
We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.
Asunto(s)
Antimaláricos/síntesis química , Chalconas/síntesis química , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Peróxidos/síntesis química , Profármacos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Chalconas/química , Chalconas/farmacología , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Concentración 50 Inhibidora , Modelos Moleculares , Peróxidos/química , Peróxidos/farmacología , Plasmodium falciparum/efectos de los fármacos , Profármacos/química , Profármacos/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of semi-synthetic trioxaquines and synthetic trioxolaquines were prepared, in moderate to good yields. Antimalarial activity was evaluated against both the chloroquine-sensitive 3D7 and resistant K1 strain of Plasmodium falciparum and both series of compounds were shown to be active in the low nanomolar range. For comparison the corresponding 9-amino acridine analogues were also prepared and shown to have low nanomolar activity like their quinoline counterparts.