Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes

Nitric oxide (NO.) has been identified as a principal regulatory molecule o f the immune system and the major cytotoxic mediator of activated immune ce lls. NO. can also react rapidly with a variety of biological species, parti cularly with the superoxide radical anion O-2(.-) at almost diffusion-limit ed rates to form peroxynitrite anion (ONOO-). ONOO- and its proton-catalyze d decomposition products are capable of oxidizing a great diversity of biom olecules and can act as a source of toxic hydroxyl radicals. As a consequen ce, a strategy for the development of molecules with potential trypanocidal activities could be developed to increase the concentration of nitric oxid e in the parasites through NO.-releasing compounds. In this way, the rate o f formation of peroxynitrite from NO. and O-2(.-) would be faster than the rate of dismutation of superoxide radicals by superoxide dismutases which c onstitute the primary antioxidant enzymatic defense system in trypanosomes, The adenosine transport systems of parasitic protozoa, which are also in c ertain cases implicated in the selective uptake of active drugs such as mel arsoprol or pentamidine, could be exploited to specifically target these NO .-releasing compounds inside the parasites. In this work, we present the sy nthesis, characterization and biological evaluation of a series of molecule s that contain both a group which would specifically target these drugs ins ide the parasites via the purine transporter, and an NO.-donor group that w ould exert a specific pharmacological effect by increasing NO level, and th us the peroxynitrite concentration inside the parasite.