Recent Achievements

Metal-Nitrosyl Complex

Nitric oxide (NO) is a crucial signaling molecule involved in various pharmacological and pathological processes, including vasodilation, immune response, and neuroplasticity. However, delivering a precise amount of NO to a specific site in vivo is challenging due to its high diffusion rate and radical character. Despite various NO carriers being studied, a technology for delivering a desired amount to a specific site with the high temporal and spatial resolution is still under investigation. In recent years, metal–nitrosyl complexes have emerged as promising candidates for delivering NO with high temporal and spatial resolution. Metal–nitrosyl complexes can be precisely controlled and selectively released, making them valuable tools for studying NO signaling and developing new treatments for various diseases.

We reported that gasotransmitters use time‐dependent dynamics to discriminate endogenous and exogenous inputs. For a real‐time stimulation of cell signaling, we synthesized a photo‐cleavable cobalt–nitrosyl complex, [Co(MDAP)(NO)(CH3CN)]2+ (MDAP = N,N′‐dimethyl‐2,11‐diaza[3,3](2,6)pyridinophane), which can stably deliver and selectively release NO with fine temporal resolution in the cytosol, and used this to study the extracellular signal‐regulated kinases (ERKs), revealing how cells use both exogenous and endogenous NO to disentangle cellular responses. This technique can be to understand how diverse cellular signaling networks are dynamically interconnected and to control drug delivery systems.

We also investigated the potential of a selective vasodilator and vascular therapy using an iron–nitrosyl complex for the treatment of retinal vascular occlusion (RVO), a common cause of visual impairment. We reported a strategy that aims to pierce clogged blood vessels with a spatiotemporally controllable nitric oxide transporter, [Fe(TBDAP)(NO)(H2O)]2+ (TBDAP = N,N′-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane), which was synthesized and precisely characterized by various physicochemical methods, including X-ray crystallography. In the animal model, normal retinal blood vessels were confirmed to be dilated by the photoresponsive iron–nitrosyl complex. Furthermore, occluded retinal blood vessels were effectively reperfused after the immediate delivery of nitric oxide using light in animal disease models. These studies suggest an unprecedentedly selective and controllable treatment option for acute vascular occlusive diseases, including cardiovascular and cerebrovascular diseases.

Nitrile Activation

A mononuclear side-on peroxocobalt(III) complex with a tetradentate macrocyclic ligand, [CoIII(TBDAP)(O2)]+, shows a novel and facile mode of dioxygenase-like reactivity with nitriles (R—C≡N; R = Me, Et, and Ph) to produce the corresponding mononuclear hydroximatocobalt(III) complexes, [CoIII(TBDAP)(R—C(═NO)O)]+, in which the nitrile moiety is oxidized by two oxygen atoms of the peroxo group. The overall reaction proceeds in one-pot under ambient conditions (ca. 1 h, 40 °C). 18O-Labeling experiments confirm that both oxygen atoms are derived from the peroxo ligand. The structures of all products, hydroximatocobalt(III) complexes, were confirmed by X-ray crystallography and various spectroscopic techniques. Kinetic studies including the Hammett analysis and isotope labeling experiments suggest that the mechanistic mode of [CoIII(TBDAP)(O2)]+ for activation of nitriles occurs via a concerted mechanism. This novel reaction would be significantly valuable for expanding the chemistry for nitrile activation and utilization.

Redox-inactive metal ions play vital roles in biological O2 activation and oxidation reactions of various substrates. Recently, we showed a distinct reactivity of a peroxocobalt(III) complex bearing a tetradentate macrocyclic ligand, [CoIII(TBDAP)(O2)]+ (1) (TBDAP = N,N′-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane), toward nitriles that afforded a series of hydroximatocobalt(III) complexes, [CoIII(TBDAP)(R–C(═NO)O)]+ (R = Me (3), Et, and Ph). In this study, we report the effects of redox-inactive metal ions on nitrile activation of 1. In the presence of redox-inactive metal ions such as Zn2+, La3+, Lu3+, and Y3+, the reaction does not form the hydroximatocobalt(III) complex but instead gives peroxyimidatocobalt(III) complexes, [CoIII(TBDAP)(R–C(═NH)O2)]2+ (R = Me (2) and Ph (2Ph)). These new intermediates were characterized by various physicochemical methods including X-ray diffraction analysis. The rates of the formation of 2 are found to correlate with the Lewis acidity of the additive metal ions. Moreover, complex 2 was readily converted to 3 by the addition of a base. In the presence of Al3+, Sc3+, or H+, 1 is converted to [CoIII(TBDAP)(O2H)(MeCN)]2+ (4), and further reaction with nitriles did not occur. These results reveal that the reactivity of the peroxocobalt(III) complex 1 in nitrile activation can be regulated by the redox-inactive metal ions and their Lewis acidity. DFT calculations show that the redox-inactive metal ions stabilize the peroxo character of end-on Co−η1-O2 intermediate through the charge reorganization from a CoII–superoxo to a CoIII–peroxo intermediate. A complete mechanistic model explaining the role of the Lewis acid is presented.