To Transfer or Not to Transfer? Development of a Dinitrosyl Iron Complex as a Nitroxyl Donor for the Nitroxylation of an Fe^III–Porphyrin Center

Abstract

A positive myocardial inotropic effect achieved using HNO/NO(-) , compared with NO⋅, triggered attempts to explore novel nitroxyl donors for use in clinical applications in vascular and myocardial pharmacology. To develop M-NO complexes for nitroxyl chemistry and biology, modulation of direct nitroxyl-transfer reactivity of dinitrosyl iron complexes (DNICs) is investigated in this study using a Fe(III) -porphyrin complex and proteins as a specific probe. Stable dinuclear {Fe(NO)2 }(9) DNIC [Fe(μ-(Me) Pyr)(NO)2 ]2 was discovered as a potent nitroxyl donor for nitroxylation of Fe(III) -heme centers through an associative mechanism. Beyond the efficient nitroxyl transfer, transformation of DNICs into a chemical biology probe for nitroxyl and for pharmaceutical applications demands further efforts using in vitro/in vivo studies.

Hemodynamic Effects of Glutathione-Liganded Binuclear Dinitrosyl Iron Complex: Evidence for Nitroxyl Generation and Modulation by Plasma Albumin

“…The redox state of NO moieties in DNICs has been uncertain. Based on X-ray studies, the Fe(NO) 2 core has been formulated as either {Fe II (NO • )(NO 2 )} 9 or {Fe III (NO 2 ) 2 } 9 , in which the NO moieties have partial negative charges (Tsai et al, 2015;Tseng et al, 2015) and thus might be expected to be released in the form of HNO. Alternatively, others have proposed the core to exist as {Fe I (NO 1 ) 2 } 7 , representing the NO moieties as positively charged (Vanin, 2009;Borodulin et al, 2013aBorodulin et al, , 2014.…”

Detection of dinitrosyl iron complexes by ozone-based chemiluminescence

“…As for HNO, there is currently little evidence that it plays a significant physiological role [37]. However due to the non-innocent nature of NO as a ligand [38–40], it is difficult to determine the exact oxidation state of the central iron, or the NO in DNICs, such that it is possible that DNICs themselves could act as nitroxyl donors if the NO in the DNICs is in the NO - form, as proposed by some investigators [41–43]. This would make it harder to differentiate whether DNICs are releasing NO in FeCN due to the oxidation of the Fe 2+ center, or due to the oxidation of a nitroxyl intermediate, or the direct oxidation of an iron-bound nitroxyl moiety.…”

Dinitrosyl Iron Complex [K‐18‐crown‐6‐ether][(NO)2Fe(MePyrCO2)]: Intermediate for Capture and Reduction of Carbon Dioxide

“…Regarding the two electrochemically reversible redox couples at E 1/2 =−0.87 and −1.18 V (vs. Fc/Fc + ) displayed by {Fe(NO) 2 } 9 –{Fe(NO) 2 } 9 DNIC [(NO) 2 Fe(μ‐ Me Pyr) 2 Fe(NO) 2 ] ( 1 ), preparation of complex 2 was attempted through chemical reduction of complex 1 by treatment of two equiv of KC 8 and 18‐crown‐6‐ether (or CoCp 2 ) (Scheme a). Successful synthesis of complex 2 was evidenced by solution/solid‐state IR, 1 H/ 13 C NMR, Fe K‐edge XAS, single‐crystal X‐ray diffraction, and theoretical calculation (Figure and Figures S1–S9 in the Supporting Information).…”