Tailoring NO Donors Metallopharmaceuticals: Ruthenium Nitrosyl Ammines and Aliphatic Tetraazamacrocycles

E.      Tfouni; F      G. Doro; L.      E. Figueiredo; J.      C.M. Pereira; G.      Metzker; D.      W. Franco

doi:10.2174/092986710793213788

Abstract

The discovery of the involvement of nitric oxide (NO) in several physiological and pathophysiological processes launched a spectacular increase in studies in areas such as chemistry, biochemistry, and pharmacology. As a consequence, the development of NO donors or scavengers for regulation of its concentration and bioavailability in vivo is required. In this sense, ruthenium nitrosyl ammines and aliphatic tetraazamacrocyles have attracted a lot of attention due to their unique chemical properties. These complexes are water soluble and stable in solution, not to mention that they can deliver NO when photochemically or chemically activated by the reduction of the coordinated nitrosonium (NO+). The tuning of the energies of the charge transfer bands, the redox potential, and the specific rate constants of NO liberation, in both solution and matrices, is desirable for the achievement of selective NO delivery to biological targets, hence making the ruthenium ammines and aliphatic tetraazamacrocyles a quite versatile platform for biological application purposes. These ruthenium nitrosyls have shown to be active in firing neurons in mouse hippocampus, performing redox reactions in mitochondria, acting in blood pressure control, exhibiting cytotoxic activities against trypanosomatids (T.cruzi and L.major) and tumor cells. This tailoring approach is explored here, being heavily supported by the accumulated knowledge on the chemistry and photochemistry of ruthenium complexes, which allows NO donors/scavengers systems to be custom made designed.

Keywords: Ruthenium, nitrosyls, nitric oxide carriers, biological applications, ruthenium nitrosyl ammines, aliphatic tetraazamacrocyles, performing redox reactions, neurotransmission, pathogens killing, N-hydroxyguanidines, pseudo-octahedral complexes, trypanosomatids, photodynamic therapy (PDT), Mouse Hippocampus, iron-cluster-containing, differential pulse polarography (DPP), mitochondrial permeability transition (MPT), HepG2 cells, Hipotensive Properties, nitric oxide synthase enzyme (NOS), ali-phatic tetraazamacrocyles, Bioavailability, Biodistribution, Toxicity, Antiparasitic Effects, mac = macrocyclic ligand, nic = nicotinamide, NRU = neutral red uptake, P(OEt)3 = triethylphosphite, PAMAM = polyamidoamine dendrimers, RCR = respiratory control ratio, T. cruzi = Trypanosoma cruzi, TI = therapeutic, = quantum yield of release of NO