Tailoring NO Donors Metallopharmaceuticals: Ruthenium Nitrosyl Ammines and Aliphatic Tetraazamacrocycles

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.

Photo-Controlled Release of NO and CO with Inorganic and Organometallic Complexes

“…Ruthenium nitrosyl complexes are generally quite robust, and this thermal stability as well as the known photo-lability of such species has drawn considerable attention to these as possible photoNORMs [20,63,67,[87][88][89][90][91][92][93][94][95][96][97][98][99][100][101]. .…”

The nature of Ru–NO bonds in ruthenium tetraazamacrocycle nitrosyl complexes—a computational study

“…22,26,33,37,38 Ruthenium nitrosyl amines and ruthenium nitrosyl with tetraazamacrocycles are good candidates as NO carriers since they are water soluble, stable in solution and capable of releasing NO by chemical or photochemical activation, not to mention their biological activity. 19,22,35,[37][38][39][40][41] The coordinated NO can also exhibit electrophilic behavior, which is modulated by not only by the electron density but also by the NO stretching frequencies. Such complexes display a nitrosonium character of coordinated NO as observed in [RuNO(NH 3 ) 5 ] 3+ and in aqueous solution they may undergo nucleophilic attack for species such as OH − despite their stability.…”

“…39 Although the slow NO release may narrow some biological applications, such as improving the population spike of neurons, 39 it can act as a prodrug for vasodilation with slow blood pressure decrease, as observed in hypertensive male Wistar rats. 19 On replacing cyclam with four amine ligands the resulting ruthenium tetraamine nitrosyl complexes, 3 ), 4-picoline (4-pic), 4-chloropyridine (4-Clpy), imidazole (imC or imN), 4-acetylpyridine (4-acpy) and L-histidine (L-hist)) and k −NO can be tuned by a judicious choice of the trans ligand L. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] In previous theoretical studies we have addressed this issue. 54,55 Unlike Thus, N-(or C-) functionalization could be a suitable approach to control the reactivity of coordinated NO.…”

“…[56][57][58] It should be stressed that controlling the properties of the complex, such as electronic spectra, reduction potential, and specific rate constant of the release of NO, is crucial for biological applications. [15][16][17][18][19][20][21][22][23]37,38,[59][60][61][62][63] Tetraazamacrocycles such as cyclam and its derivatives are fairly flexible; they adopt five different configurations, depending on the spatial alignment of the NH protons (Fig. 1).…”

Estudo teórico-experimental de nitroxil e nitroxil complexos em tetraaminas de rutênio(II)

“…Apesar disso, os conjuntos de bases do tipo GTO têm sido mais comumente usados. Para íons ou moléculas com pares isolados adjacentes, os conjuntos de bases precisam ser aumentados com funções difusas, para permitir que a densidade eletrônica se expanda a um volume maior, para isso adiciona-se o termo "+" na função de base 30 . As legendas em negrito não fazem parte da matriz-Z, são de finalidade didática.…”