Anti-asthmatic effect of nitric oxide metallo-donor FOR811A [cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3] in the respiratory mechanics of Swiss mice

Abstract

We aimed at evaluating the anti-asthmatic effect of cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3 (FOR811A), a nitrosyl-ruthenium compound, in a murine model of allergic asthma. The anti-asthmatic effects were analyzed by measuring the mechanical lung and morphometrical parameters in female Swiss mice allocated in the following groups: untreated control (Ctl+Sal) and control treated with FOR811A (Ctl+FOR), along asthmatic groups untreated (Ast+Sal) and treated with FOR811A (Ast+FOR). The drug-protein interaction was evaluated by in-silico assay using molecular docking. The results showed that the use of FOR811A in experimental asthma (Ast+FOR) decreased the pressure-volume curve, hysteresis, tissue elastance, tissue resistance, and airway resistance, similar to the control groups (Ctl+Sal; Ctl+FOR). However, it differed from the untreated asthmatic group (Ast+Sal, p<0.05), indicating that FOR811A corrected the lung parenchyma and relaxed the smooth muscles of the bronchi. Similar to control groups (Ctl+Sal; Ctl+FOR), FOR811A increased the inspiratory capacity and static compliance in asthmatic animals (Ast+Sal, p<0.05), showing that this metallodrug improved the capacity of inspiration during asthma. The morphometric parameters showed that FOR811A decreased the alveolar collapse and kept the bronchoconstriction during asthma. Beyond that, the molecular docking using FOR811A showed a strong interaction in the distal portion of the heme group of the soluble guanylate cyclase, particularly with cysteine residue (Cys141). In summary, FOR811A relaxed bronchial smooth muscles and improved respiratory mechanics during asthma, providing a protective effect and promising use for the development of an anti-asthmatic drug.

Ruthenium-nitrosyl complexes as NO-releasing molecules, potential anticancer drugs, and photoswitches based on linkage isomerism

“…Antileishmanial 213,214 and anti-inflammatory (as caused by gout arthritis) 215 activities of cis -[Ru(L) 2 (SO 3 )(NO)](PF 6 ), where L = bipyridine, were also reported recently. Anti-asthmatic complexes, cis -[Ru(L 1 ) 2 (L 2 )(NO)](PF 6 ) 3 , where L 1 = 2,2′-bipyridine, L 2 = 2-methyl-1 H -imidazole, 216 and [Ru(NO)(L 1 )(L 2 )] 3+ , where L 1 = terpyridine, L 2 = 1,2-benzoquinone-diimine, 217 were recently reported as well. Some attention was also payed to ruthenium nitrosyl compounds as nitric oxide donors for the treatment of cardiovascular diseases.…”

Nitric Oxide as a Central Molecule in Hypertension: Focus on the Vasorelaxant Activity of New Nitric Oxide Donors

“…The cis-[Ru(bpy) 2 (2-MIM)(NO)](PF 6 ) 3 (FOR811A) was studied in a murine model of allergic asthma and it decreased the alveolar collapse and preserved the bronchoconstriction during asthma. In addition, molecular docking using FOR811A showed a strong interaction with the heme group of cGC [262]. Another compound, cis-[Ru(NO 2 )(bpy) 2 (5NIM)]PF 6 complex showed a potential pharmacological application as an antioxidant and anti-inflammatory (inhibition of pro-inflammatory cytokines) in in vitro studies [263].…”

New nitrosyl ruthenium complexes with combined activities for multiple cardiovascular disorders

“…Those efforts resulted in promising compounds such as NAMI-A, KP1019, RAPTA-C and others, which were able to cause cell death through mechanisms distinct from platinum drugs. 21–23 Moreover, in the following years, several Ru-based species were synthesized exhibiting diverse therapeutic activities as antitumoral, 24,25 bactericide, 26–28 anti-parasitic, 29–31 and anti-inflammatory 32–34 agents, revealing great potential for pharmacological application.…”