About Ashley Bill's Research

Ashley Bill ’17 is currently working under the supervision of Doreen Szollosi, Ph.D. and Ola Ghoneim, Ph.D. at the Pharmaceutical Sciences Laboratory, School of Pharmacy. Ashley Bill '17 is the recipient of one of the USJ Undergraduate Grants for 2015-2016 sponsored by the Provost’s Office. Ashley is presently making great progress on the following two projects:

Novel piperazino-enaminone derivatives to suppress pro-inflammatory cytokines and inhibit chemokine receptor CCR2

ashley-bill-265x350.jpgPro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn’s disease and Rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino-enaminone analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.  Ms. Bill is currently undertaking a structure activity relationship of the JODI series, where she is expanding on the chemical synthesis to encompass a wide range of N-methylpiperazine on different position on the aromatic ring, as well as varying the substitution on position 2 of the enaminone ring. Ashley has synthesized more than 10 novel analogs. Biological testing is conducted by Dr. Szollosi at the School of Pharmacy. Manuscript is in preparation for Journal of Bioorganic and Medicinal Chemistry Letters.

Collaborators: Dr. Doreen Szollosi, Assistant Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph

Hands-on experiment to enhance student learning on nucleophilic aromatic substitution reactions

Our laboratory has always been interested in developing serotonergic hybrids combining serotonin autoreceptors antagonism and serotonin transporters inhibition with the main goal to reduce the repetitive behaviors in children with autism. During our journey, we discovered an efficient and robust amination route utilizing nucleophilic aromatic substitution (NAS) reaction. This reaction uses isopropyl alcohol as the sole reagent/solvent. The high yields, lack of side reactions, wide range of amines used, and short reaction times (5-10 minutes average), make them highly attractive to be used as a teaching tool for the undergraduate chemistry laboratory. NAS is a process where a nucleophile attacks an electron deficient aromatic ring. This results in a carbanion intermediate stabilized by the electron withdrawing groups (EWG) attached to the ring. Loss of the leaving group (LG), typically a halogen, resulted in an overall substitution of the nucleophile for the halogen. Since stabilization of the anion is required for the reaction to proceed, EWG must be ortho and/or para to the site of nucleophilic attack. Methyl-4-fluoro-3-nirobenzoate was used as starting material since it fulfills the criteria of having a halogen as LG and a nitro group as EWG in the ortho position. Out of the 15 amines that were conducted, only 5 amines as the nucleophiles were selected to be executed in the CHEM210 laboratory at the University of Saint Joseph. The reaction condition, yield, and all products were fully characterized. The reflection of enhancing student learning on nucleophilic aromatic substitution reaction was also collected. The work has been presented as a poster presentation at Eastern Colleges Science Conference, Springfield, MA, April 2, 2016, and at University of Saint Joseph-Symposium Day. The poster was also selected to be displayed at the Presidential Inauguration Research Night. A manuscript to Journal of Chemical Education is ready to be submitted.

Collaborator: Dr. Steven Goldstein, Associate Professor, Chemistry Department, School of Health and Natural Sciences, University of Saint Joseph.

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