Research Projects

Nitric oxide (NO) plays pivotal roles in vasodilation, cytoprotection, and neurotransmission. However, NO is readily converted to nitrate (NO₃⁻) and nitrite (NO₂⁻) and thus has a brief lifespan in biological media. Consequently, NO₂⁻ and S-nitrosothiols act as the biological reservoirs of NO in mammalian physiological processes. Reduction of NO₂⁻ to NO and H₂O is mediated mainly by iron and copper in the biological systems. Globins, cytochrome c oxidase, xanthine oxidoreductase and YtfE also reduce NO₂⁻ to NO. Thiols (RSH) react with NO₂⁻ in the gut to generate RSNOs, which, in turn, produces NO and disulfides (RS-SR). The copper ion also promotes the generation of NO from RSNOs. Hydrogen sulfide (H₂S) acts as an endogenous gasotransmitter and its implications in neuromodulation and vasodilation are well recognized. NO and H₂S also cross paths in cell signaling and involves many reactive “crosstalk” intermediates such as thionitrite (SNO⁻), perthionitrite (SSNO⁻) and their protonated forms, out of which HSNO is involved in nitroxyl (HNO) dependent signaling processes. HSSNO (pKa = 0.02) primarily exists as SSNO⁻ under physiological conditions and can generate NO both in the presence and in the absence of protons. Consequently, SSNO⁻ can effectively activate NO-receptors, such as in soluble guanylate cyclase (sGC). Furthermore, considering the capability of SSNO⁻ as the source of sulfane sufur and polysulfide, the biological targets of SSNO⁻ might also include Nrf2 transcription factor, which regulates the cellular resistance against oxidative stress. Thus, NO, H₂S/HS⁻, thiols and SNO⁻, SSNO⁻ are highly important for many of our physiological processes. In this project we propose to investigate transition metal mediated generation of NO and the reactivity of NO and NO₂⁻ with S-donor ligands for the generation of the reactive sulfur-nitrogen “crosstalk” species, namely, SNO⁻, SSNO⁻. The investigations in this project will include reactivity of new transition metal-nitrite complexes with thiols, hydrosulfide and polychalcogenides. Reactivity of new transition metal-polysulfido/-polyselenido complexes and their reactivity with NO and NO₂⁻ will be investigated for the generation of SNO⁻, SSNO⁻, and their selenium analogues. Further reactivity of these sulfur-nitrogen “crosstalk” species will be investigated which will allow new chemical transformations. Initial accounts on the synthesis of novel transition metal-polychalcogenido complexes, transition metal mediated generation of NO and the reactivity of NO₂⁻ with polysulfide and with thiocarboxylates to generate NO, RC(O)ONO and SSNO⁻ have recently been published by us (J. Am. Chem. Soc. 2025, 147, 15408-15428; Inorg. Chem. 2025, 64, 7726-7745; Inorg. Chem. 2024, 63, 15161-15176; JACS Au. 2024, 2, 771-787), which strengthen the backbone of this research proposal. We will work towards the development of efficient stoichiometric and catalytic reduction of NO₂⁻ to NO, their reactivity with thiols, hydrosulfide and polychalcogenides and establish the reaction mechanism using UV-vis, EPR, IR (with ¹⁵N isotope labeling) and NMR (¹H and ¹⁵N) spectroscopy, mass spectrometry, cyclic voltammetry and single crystal X-ray structure determination of the starting metal complexes, intermediates generated and the final products. Theoretical calculation at the DFT level will be performed to understand the electronic structure of the key complexes, to corroborate the observed spectroscopic data of the intermediates generated and to elucidate the reaction mechanisms involved. Successful implementation of this project will therefore significantly enhance the existing knowledge regarding generation of NO, reactivity of NO and NO₂⁻ with S-donor ligands for the generation of SNO⁻, SSNO⁻ and further reactivity of the latter species in relation with physiologically important processes.