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Collaborative experiences have been widely integrated into the classroom and laboratory, with goals to build time management, communication, and team-working skills. Most reported laboratory collaborations occur between students within the same lab section, which could limit the potential benefits of these experiences. Presented herein is an organic chemistry laboratory model in which students collaborate across lab sections (i.e., interlab collaborations) to complete discovery-based, medicinal-chemistry-focused experiments. These experiences provide opportunities for students to reflect on and improve upon their team-working skills. Over the past three years, interlab collaborations have been offered at Muhlenberg College to 105 students in two types of organic chemistry courses. Assessment data, including notebook evaluation scores, peer- and self-evaluations, lab report scores, and student reflections, suggest that these experiences could help build time management, communication, organizational, and data-recording skills. These laboratories could give students a realistic view of collaborative work and allow for the intentional development and assessment of team-working skills in any introductory or upper-level chemistry laboratory. Furthermore, this model provides a framework for reducing lab section sizes by half, a change which has been needed during COVID-19, while still completing the planned lab curriculum.

Sulfur mustard (SM, bis(2-chloroethyl sulfide) is a potent vesicating agent known to cause skin inflammation, necrosis and blistering. Evidence suggests that inflammatory cells and mediators that they generate are important in the pathogenic responses to SM. In the present studies we investigated the role of mast cells in SM-induced skin injury using a murine vapor cup exposure model. Mast cells, identified by toluidine blue staining, were localized in the dermis, adjacent to dermal appendages and at the dermal/epidermal junction. In control mice, 48–61% of mast cells were degranulated. SM exposure (1.4 g/m(3) in air for 6 min) resulted in increased numbers of degranulated mast cells 1–14 days post-exposure. Treatment of mice topically with an indomethacin choline bioisostere containing prodrug linked by an aromatic ester-carbonate that targets cyclooxygenases (COX) enzymes and acetylcholinesterase (1% in an ointment) 1–14 days after SM reduced skin inflammation and injury and enhanced tissue repair. This was associated with a decrease in mast cell degranulation from 90% to 49% 1–3 days post SM, and from 84% to 44% 7–14 days post SM. These data suggest that reduced inflammation and injury in response to the bifunctional indomethacin prodrug may be due, at least in part, to abrogating mast cell degranulation. The use of inhibitors of mast cell degranulation may be an effective strategy for mitigating skin injury induced by SM.

The laboratory is a mainstay in STEM education, promoting the development of critical thinking skills, dexterity, and scientific curiosity. The goals in the laboratory for nonchemistry, prehealth majors, though, could be distinguished from those for chemistry majors. In service courses such as organic chemistry, much laboratory time is often spent building discipline-specific technical skills that poorly align with the postgraduate goals of prehealth students. To address the needs of students in Muhlenberg College’s organic chemistry course for nonchemistry majors, we developed a time- and resource-saving laboratory sequence that alternates traditional experiments with computer-graded self-guided inquiry activities. This innovative sequence requires approximately half the amount of reagents and fewer staff members, and it offers increased flexibility for students and instructors compared to a traditional (i.e., weekly) lab experience. When this model was offered in 2013–15, student performances on reports...

The molecular pathology of sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate preattachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years.

PURPOSE Sulfur mustard, nitrogen mustard (NM), and 2-chloroethyl ethyl sulfide all cause corneal injury with epithelial-stromal separation, differing only by degree. Injury can resolve in a few weeks or develop into chronic corneal problems. These vesicants induce microbullae at the epithelial-stromal junction, which is partially caused by cleavage of transmembranous hemidesmosomal collagen XVII, a component anchoring the epithelium to the stroma. ADAM17 is an enzyme involved in wound healing and is able to cleave collagen XVII. The activity of ADAM17 was inhibited in vesicant-exposed corneas by four different hydroxamates, to evaluate their therapeutic potential when applied 2 hours after exposure, thereby allowing ADAM17 to perform its early steps in wound healing. METHODS Rabbit corneal organ cultures exposed to NM for 2 hours were washed, then incubated at 37°C for 22 hours, with or without one of the four hydroxamates (dose range, 0.3-100 nmol in 20 μL, applied four times). Corneas were analyzed by light and immunofluorescence microscopy, and ADAM17 activity assays. RESULTS Nitrogen mustard-induced corneal injury showed significant activation of ADAM17 levels accompanying epithelial-stromal detachment. Corneas treated with hydroxamates starting 2 hours post exposure showed a dose-dependent ADAM17 activity inhibition up to concentrations of 3 nmol. Of the four hydroxamates, NDH4417 (N-octyl-N-hydroxy-2-[4-hydroxy-3-methoxyphenyl] acetamide) was most effective for inhibiting ADAM17 and retaining epithelial-stromal attachment. CONCLUSIONS Mustard exposure leads to corneal epithelial sloughing caused, in part, by the activation of ADAM17 at the epithelial-stromal junction. Select hydroxamate compounds applied 2 hours after NM exposure mitigated epithelial-stromal separation.

Nuclear magnetic resonance (NMR) spectroscopy is an integral part of the undergraduate chemistry curriculum. In addition to structure determination, NMR spectroscopy is used to analyze chemical reactions and equilibria in situ. Determination of the position of equilibria is well-suited to NMR analysis in the undergraduate laboratory as an extension of peak identification and signal integration, and the determination of keto–enol equilibrium remains a popular undergraduate laboratory experiment. Several factors affect the position of keto–enol equilibrium, defined here as Ke/k = [enol]/[keto], including structure (steric bulk, conjugation, electron-withdrawing/donating groups, resonance), temperature, and solvent. A judiciously selected set of compounds that have a common 1,3-dicarbonyl moiety with progressively changing ligands at the 1 and 3 positions is presented. This array allows students to investigate structure–function relationships that affect keto–enol equilibrium in a cumulative fashion and affo...

Novel ethynylphenyl carbonates and carbamates containing carbon- and silicon-based choline mimics were synthesized from their respective phenol and aniline precursors and screened for anticholinesterase and anti-inflammatory activities. All molecules were micromolar inhibitors of acetylcholinesterase (AChE), with IC50s of 28–86 μM; the carbamates were two-fold more potent than the carbonates. Two of the most potent AChE inhibitors suppressed 12-O tetradecanoylphorbol-13-acetate (TPA)-induced inflammation by 40 %. Furthermore, these molecules have physicochemical properties in the range of other CNS drugs. These molecules have the potential to treat inflammation; they could also dually target Alzheimer’s disease through restoration of cholinergic balance and inflammation suppression.

The molecular pathology of a sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate pre-attachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years.

As part of a continuous effort to develop efficient counter measures against sulfur mustard injuries, several unique NSAID prodrugs have been developed and screened for anti-inflammatory properties. Presented herein are three classes of prodrugs which dually target inflammation and cholinergic dysfunction. Compounds 1-28 contain common NSAIDs linked either to choline bioisosteres or to structural analogs of acetylcholinesterase (AChE) inhibitors. These agents have shown utility as anti-vesicants and anti-inflammatory agents when screened in a mouse ear vesicant model (MEVM) against both 2-chloroethyl ethyl sulfide (CEES), a blistering agent, and 12-O-tetradecanoylphorbol-13-acetate (TPA), a common topical irritant. Many of the prodrugs have activity against CEES, with 5, 18, 22 and 27 reducing inflammation by more than 75% compared with a control. Compounds 12, 13, 15 and 22 show comparable activity against TPA. Promising activity in the MEVM is related to half-lives of NSAID release in plasma, moderate to high lipophilicity, and some degree of inhibition of AChE, a potential contributor to sulfur mustard-mediated tissue damage.

Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme mediating activation of cholinergic inflammatory pathways in a model of SM-induced skin injury. Adult SKH-1 hairless male mice were exposed to SM using a dorsal skin vapor cup model. NDH 4338 was applied topically to the skin 24, 48, and 72 hr post-SM exposure. After 96 hr, SM was found to induce skin injury characterized by edema, epidermal hyperplasia, loss of the differentiation marker, keratin 10 (K10), upregulation of the skin wound marker keratin 6 (K6), disruption of the basement membrane anchoring protein laminin 322, and increased expression of epidermal COX2. NDH 4338 post-treatment reduced SM-induced dermal edema and enhanced skin re-epithelialization. This was associated with a reduction in COX2 expression, increased K10 expression in the suprabasal epidermis, and reduced expression of K6. NDH 4338 also restored basement membrane integrity, as evidenced by continuous expression of laminin 332 at the dermalepidermal junction. Taken together, these data indicate that a bifunctional anti-inflammatory prodrug stimulates repair of SM induced skin injury and may be useful as a medical countermeasure.