Document Type

Thesis - Open Access

Award Date

2020

Degree Name

Master of Science (MS)

Department

Chemistry and Biochemistry

First Advisor

Brian Logue

Keywords

Antidote, CEES, Chemical Warfare Agent, Scavenger, Sulfur Mustard, Therapeutic

Abstract

Sulfur mustard is a highly toxic and dangerous vesicant that has been utilized as a chemical warfare agent (CWA) since World War I. Despite its extensive history, an effective antidote to sulfur mustard exposure still does not exist. With detectable levels of unreacted sulfur mustard lasting days after initial contact, a window of opportunity exists to administer a “scavenger” to affected individual immediately and in the days following exposure in hopes of reducing harm by neutralizing unreacted sulfur mustard. For this strategy to be effectively implemented, it is essential to identify a candidate compound with excellent affinity towards sulfur mustard and very low toxicity. A deliberate stepwise process of scavenger identification was accomplished in this study. First, a group of compounds with select functional group nucleophilicity (i.e., first-generation scavengers) towards chloroethyl ethyl sulfide (CEES) (i.e., CEES is a non-CWA surrogate for sulfur mustard) was evaluated. A series of two-carbon molecules with multiple scavenging functionalities were initially tested for effectiveness in protecting human keratinocyte (HaCat) cells via MTT cell viability and cell-matrix adhesion (CMA) assays. HaCat cells were used to mimic dermal exposure. The firstgeneration scavengers, a set of five two-carbon compounds with various functional groups, served as a preliminary group of scavengers to survey the correlation between scavenging ability and functional group nucleophilicity. These trials generally validated the trend of increasing scavenging-ability mirroring increasing nucleophilicity, with the exception of thioacids, which produced additive toxicity. Next, second-generation candidate scavengers (i.e., drug molecules containing promising structural features identified from the first-generation scavengers) were identified and their performance as scavengers was evaluated. With thiols and amines proving to be the most promising functional groups in terms of both excellent nucleophilicity and minimal toxicity, the second-generation candidate scavengers were selected to explore the effectiveness of these functionalities. Out of this group of seven second-generation scavengers, the thiodiamine functional group, found in the candidate scavenger methimazole, most effectively reduced cell death and loss of cell-matrix adhesion caused by CEES. Overall, this bottom-up comprehensive search for promising scavengers has narrowed the field of potential candidate molecules to those possessing thiols, thioamines, and thiodiamines.

Format

application/pdf

Number of Pages

62

Publisher

South Dakota State University

Rights

In Copyright - Non-Commercial Use Permitted
http://rightsstatements.org/vocab/InC-NC/1.0/

Available for download on Friday, June 16, 2023

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