THE REACTION MECHANISM OF NITROPRUSSIDE WITH HS? (GMELIN PROCESS). EVIDENCE OF BOUND NOSH, NSOH, NOS?, NOS2?, NO?, HNO AND N2O22? INTERMEDIATES.

BARI, SARA E.; AMOREBIETA, VALENTÍN T.; BIEZA, SILVINA ANDREA; OLABE, JOSÉ A.; SLEP, LEONARDO D.

Nápoles

Conferencia; 4th International Conference on the Biology of Hydrogen Sulfide; 2016

Department of Pharmacy - Federico II University of Naples

Nitroprusside [Fe(CN)5(NO)]2− is an electrophilicanion reactive toward diverse types of O-, N-, and S-binding nucleophiles. HS−forms reversibly [Fe(CN)5(NOSH)]3−, an adduct thatequilibrates very rapidly with its isomer [Fe(CN)5(NSOH)]3−and with the deprotonated [Fe(CN)5(NOS)]4− ion containingthe nitrososulfide (thionitrite) ligand NOS− (Ired: λmax,535 nm; ε = 6 ± 0.3 × 103 M−1 cm−1).[1,2,3]The stretching frequency νNO at 1370 cm−1 indicatesa strongly reduced nitrosyl-species with formally a nitroxyl (NO−)ligand in the delocalized [S−N=O]− moiety. Ired reactsspontaneously by homolysis of the N-S bond giving sulfur radicals S·−which add to HS− forming highly reactive HS2.2− radicalsfavoring a catalytic generation of [Fe(CN)5(NO·)]3−and hydrodisulfide, HS2−. Ired adds sulfurthrough a HS2−/HS− interchange(transnitrosation reaction), giving [Fe(CN)5(NOS2)]4−(I550: λmax, 550 nm), also formed through the reaction of[Fe(CN)5(NO)]2− with HS2−. I550contains the nitrosodisulfide (perthionitrite) ligand NOS2−,and transforms into the disulfur-bridged dimer, [(NC)5FeN(O)S-S(O)NFe(CN)5]6−(I575: λmax, 575 nm). Both I550 and I575display an equilibrium redox network also comprising [Fe(CN)5(NO·)]3−/[Fe(CN)4(NO)·]2−and [Fe(CN)5(HNO)]3−, the one- and two-electronreduction products of [Fe(CN)5(NO)]2−, respectively.Under excess HS−, I575 forms a hyponitrite-bridgedradical complex, [(NC)5FeN(OH)=(O·)NFe(CN)5]6− (I290: λmax,290 nm) followed by disproportionation into the closed-shell bridged analog,with concomitant release of [Fe(CN)5(NO·)]3−.The hyponitrous/hyponitrite dimers can be subsequently reduced by HS−through proton-coupled electron transfers in the pH-range 7-12 leading to[Fe(CN)5(NH3)]3−, which forms [Fe(CN)5(H2O)]3−andfree NH3.Early production of N2O arises at pH?s > 11 through acompetitive decomposition of the hyponitrite dimer, and in a slower way throughNO-release from [Fe(CN)5(NO·)]3−, rapiddinitrosyl formation and disproportionation into [Fe(CN)5(NO)]2−and N2O. The overall reduction process involves a series ofligand-based redox reactions, from bound NO+ down to NH3.Free NO was detected in very low yields, and some HNO probably generates at theμM/nM level from the very inert [Fe(CN)5(HNO)]3−intermediate. S8 is the unique product of sulfide oxidation, and[Fe(CN)5(H2O)]3− decomposes slowly into[Fe(CN)6)]4− and free Fe(II) aqua-ions.The mechanism illustrates an active ?NO/H2S? cross-talkinvolving three redox-states of nitrosyl (NO+, NO?, NO?/HNO)and sulfur (HS?, HS2?, So),and a discussion will be given on the biochemical significance of some of thesespecies as potential signaling agents.[3]  [1] Quiroga SL, Almaraz AE, Amorebieta VT, Perissinotti LL, Olabe JA. Addition and redox reactivity of hydrogen sulfides (H2S/HS⁻) with nitroprusside: new chemistry of nitrososulfide ligands. Chemistry. 2011 Apr 4;17(15):4145-56. PubMed PMID: 21404343.[2] Filipovic MR, Eberhardt M, Prokopovic V, Mijuskovic A, Orescanin-Dusic Z, Reeh P, Ivanovic-Burmazovic I. Beyond H2S and NO interplay: hydrogen sulfide and nitroprusside react directly to give nitroxyl (HNO). A new pharmacological source of HNO. J Med Chem. 2013 Feb 28;56(4):1499-508. PubMed PMID: 23418783.[3] Cortese-Krott MM, Kuhnle GG, Dyson A, Fernandez BO, Grman M, DuMond JF, Barrow MP, McLeod G, Nakagawa H, Ondrias K, Nagy P, King SB, Saavedra JE, Keefer LK, Singer M, Kelm M, Butler AR, Feelisch M. Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl. Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):E4651-60.PubMed PMID: 26224837.