In vitro and in vivo antiproliferative and trypanocidal activities of ruthenium NO donors

Abstract

Background and purpose: Many compounds liberating NO (NO donors) have been used as therapeutic agents. Here we test two ruthenium nitrosyls, which release NO when activated by biological reducing agents, for their effects in vitro and in vivo against Trypanasoma cruzi, the agent responsible for the American trypanosomiasis (Chagas' disease). Experimental approach: Ruthenium NO donors were incubated with a partially drug-resistant strain of T. cruzi and the anti-proliferative and trypanocidal activities evaluated. In a mouse model of acute Chagas' disease, trypanocidal activity was evaluated by measuring parasitemia, survival rate of infected mice and elimination of amastigotes in myocardial tissue. Key results: In vitro, the observed anti-proliferative and trypanocidal activities of trans-[Ru(NO)(NH 3) 4isn](BF 4) 3 and trans-[Ru(NO)(NH 3) 4imN] (BF 4) 3 were due to NO liberated upon reduction of these nitrosyls. Ru(NO)isn had a lower IC 50epi (67 μM) than the NO donor, sodium nitroprusside (IC 50epi=244 μM) and Ru(NO)imN (IC 50try=52 μM) was more potent than gentian violet (IC 50try=536 μM), currently used in the treatment of blood. Both ruthenium nitrosyls eliminated, in vivo, extracellular as well as intracellular forms of T. cruzi in the bloodstream and myocardial tissue and allowed survival of up to 80% of infected mice at a dose (100 nmol kg -1 day -1) much lower than the optimal dose for benznidazole (385 μmol kg -1 day -1). Conclusions and implications: Our data strongly suggest that NO liberated is responsible for the anti-proliferative and trypanocidal activities of the ruthenium NO donors and that these compounds are promising leads for novel and effective anti-parasitic drugs. © 2007 Nature Publishing Group All rights reserved.