| dc.description.abstract | Thiolates and their metal complexes have long been central to biological and inorganic chemistry. In addition to their ability to form unidentate complexes, thiolates are well known to act as bridges between metal centers and can be readily modified by oxidation, alkylation, and acetylation, facilitating the construction of highly modified metal complexes. The work described here focuses on the utility of thiolate-based ligands to serve as a platform for investigations into the solution-phase properties of nickel complexes, as well as the inhibition of SARS-CoV-2 by metalthiolates.
While molecular structures obtained via X-ray Diffraction (XRD) are often the benchmark for inorganic structural determination, other techniques can offer insights not readily available in the solid-state. Various synthetic routes to a self-assembled tetrameric nickel cage with carboxylate linkages, [Ni(N₂S’ O)I(CH₃CN)]₄⁰, [Ni-I]₄⁰, were explored with the differences between the solid state and solution-phase aggregation investigated. In each case, hexacoordinate nickel units ligated by N₂S-thioether, iodide, and two carboxylate oxygens, one of which is the bridge from the adjacent nickel unit in [Ni-I]₄⁰, were observed in the molecular structure. In solution however, there is dissociation into (presumed) monomers with coordinating solvents occupying the 6th coordination site [Ni(N₂S’O)I(solv)]⁰, [Ni-I]⁰. Hydrodynamic radii (rH) determined from ¹H DOSY NMR data supports this hypothesis, with the rH in both D₂O and CD₂Cl₂ matching that of a monomeric unit from the tetrameric solid-state structure. These studies point to the importance of using techniques such as DOSY to interrogate the solution-phase properties of inorganic complexes that may be unavailable in the solid state.
Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2Mpro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, long used as a medicinal supplement and known to support immune function, bind to the SC2Mpro enzyme in combination with lipophilic tropolone and thiotropolone ligands, L, block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, in vitro protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC₅₀, for SC2Mpro in the 8-34 µM range, the IC₅₀ values are ca. 100 nM for Zn(NO₃)₂ which are further enhanced in Zn-L combinations (59-97 nM). Isolation of the Zn(L)₂ binary complexes and characterization of their ability to undergo ligand displacement is the basis for computational modeling of the chemical features of the enzyme inhibition. Blind docking onto the SC2Mpro enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn-L combinations orient so as to permit dative bonding of Zn(L)⁺ to basic active site residues.
With the emergence of new variants of SARS-CoV-2 that have been shown to have increased virulence, the search for effective inhibitors remains a priority. Expanding on our previous work, other first row transition metals (Fe-Cu) and their complexes with L are compared to that of Zn(L)₂, known inhibitors of SC2Mpro in an effort to identify potential therapeutics. It was determined that none of the other metals, neither as MClₓ salts (Kᵢ values between ca. 170 - 640 µM), nor as complexes with L (Kᵢ’s ca. 30 - 75 µM), provide the same level of inhibition as Zn(L)₂ (Kᵢ values ca. 430 - 900 nM). The effects of changing coordination environment around Znᴵᴵ are also explored, with a 2S dithiotropolone ligand (L4) being compared with the previously investigated SO-donor thiotropolones. Here, the additional S-donor results in poorer inhibitory activity for the Zn(L4)₂ complex (Kᵢ ca. 41 µM). Native Mass Spectrometry studies point to formation of Zn(L)-SC2Mpro adducts as a potential mode of inhibition. | |
