RESUMEN
Improving the selectivity of anticancer drugs towards cancer cells is one of the main goals of drug optimization; the prodrug strategy has been one of the most promising. A light-triggered prodrug strategy is presented as an efficient approach for controlling cytotoxicity of the substitutionally inert cytotoxic complex [Ru(dppz)2(CppH)](PF6)2(C1; CppH=2-(2-pyridyl)pyrimidine-4-carboxylic acid; dppz=dipyrido[3,2-a:2',3'-c]phenazine). Attachment of a photolabile 3-(4,5-dimethoxy-2-nitrophenyl)-2-butyl (DMNPB) ester ("photocaging") makes the otherwise active complex C1 innocuous to both cancerous (HeLa and U2OS) and non-cancerous (MRC-5) cells. The cytotoxic action can be successfully unleashed in living cells upon light illumination (350â nm), reaching similar level of activity as the parent cytotoxic compound C1. This is the first substitutionally inert cytotoxic metal complex to be used as a light-triggered prodrug candidate.
Asunto(s)
Antineoplásicos/farmacología , Ácidos Carboxílicos/química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Pirimidinas/química , Rutenio/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Células HeLa , Humanos , Fotólisis , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacologíaRESUMEN
We present the design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the organic antimalarial mefloquine, a drug also known for its antischistosomal activity. The two metallocenyl derivatives prepared (3 and 4) demonstrated comparable activity to mefloquine against adult-stage Schistosoma mansoni in vitro. Importantly, both compounds were found to have lower toxicity in all cell lines than mefloquine itself. Administration of a 200 mg kg-1 oral dose of 3 and 4 to S. mansoni-infected mice did not significantly reduce worm burden, contrary to mefloquine.