Date of Graduation

12-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry (PhD)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor/Mentor

Stites, Wesley E.

Committee Member

Kilyanek, Stefan M.

Second Committee Member

Millett, Francis S.

Third Committee Member

Sakon, Joshua

Keywords

Essential Elements; Micronutrient; Mustard Gas; Sulfur Mustard

Abstract

Model compounds, 3,6,9-trithaiundecane-1,11-dicarboxylic acid (TTDPA), 2,5,8-trithianonane-1,9-dicarboxylic acid (TTDAA), and 1,11-diamide-3,6,9-trithiaundecane (TTDAce), closely related to the adducts formed by cysteine alkylation of the chemical weapon, sulfur mustard, were synthesized. It is shown that TTDPA forms complexes with key metal micronutrients: copper, nickel, cobalt, manganese, and zinc. Though the strength of binding to TTDPA varies, the complexes in many cases precipitate from solution. All metals produced a visible precipitate upon interaction with TTDPA under the conditions tested, however only Cu2+, Mn2+, and Zn2+ produced enough to be measured. The mass of formed precipitate seemed to peak at an equimolar ratio of TTDPA to metal even when the concentration of the metal was in a 5-fold excess. However, in the case of Mn2+ the reaction occurred so slowly that very little precipitate was recovered in the equimolar ratio, but a large amount was observed days later. Crystal structure data shows that the tridentate thioether portion of TTDPA is sufficient to form a complex with a Cu2+ ion and a chloride, meaning that the alkylation adducts formed by cysteine or larger cysteine containing peptides or proteins contain all the functionality needed to bind to copper. Surprisingly, there were two distinct crystals formed from interactions of TTDPA with CuCl2. In both forms, the three sulfurs of the adduct model bind to a single Cu2+ with a coordination number of four. The remaining site in the tetrahedral complex is a chloride, but with key differences in how this chloride interacts in the two forms. The first form was a clear crystal with a dimeric structure and two TTDPA:Cu2+ complexes bridged by a single chloride ion (µCl-bis-(Cu-L)). The second form was a green crystal and was a monomeric structure without bridged Cu2+ ions (L-CuCl) in the key interaction between the three sulfurs of the adduct model. However, the carboxylate groups at the ends of the ligand in the green crystal coordinate to an additional Cu2+ ion, forming an octahedral complex with two TTDPA ligands, one water molecule and another Cu2+ ion. Even with the addition of the copper bound carboxylate, the copper – tridentate ligand interaction was enough to give sufficient binding and stability. Although these two structures existed in all ratios of ligand to metal, in the captured precipitate the µCl-bis-(Cu-L) was always the dominate product. The ready formation of these complexes leads us to hypothesize that localized depletion of such metals could ensue due to complex formation with the thiol alkylation products of sulfur mustard. These metal micronutrients play pivotal roles in burn wound healing and cellular protection from oxidative stress. The effective reduction of Cu2+, Mn2+, and Zn2+ concentration could, for example, limit function of superoxide dismutase enzymes leading to an increase in oxidative stress on the cell. Copper is itself toxic and pulling it out of enzymes and the carefully regulated copper transport and storage system to form complexes which might catalyze the formation of reactive oxygen species is another potential concern. Thus, the findings proposed in this research suggest a new hypothesis explaining the increased toxicity of sulfur mustard relative to similar monofunctional alkylating agents and the unexplained symptoms of mustard exposure.

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