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BACKGROUND: The protein tyrosine phosphatase non receptor type 22 (PTPN22) gene inhibits T-cell activation. A functional single nucleotide polymorphism (SNP) Arg620Trp (rs2476601), resulting from a C→T substitution at nucleotide position 1858, is a significant risk factor for rheumatoid arthritis (RA) in European populations. The variant allele results in a gain of function that alters the threshold for T-cell signalling and abnormal T regulatory cell function. AIM: To investigate the role of the PTPN22 R620W polymorphism in disease susceptibility and severity in Black South Africans (BSA) with RA. METHODS: A cohort of 187 BSA patients with RA and 93 ethnically matched Black and 60 White controls with no history of RA or other autoimmune diseases were studied. Genotyping was performed by the polymerase chain reaction and pyrosequencing. RESULTS: The rs2476601 SNP was nonpolymorphic in both Black patients and Black control subjects with total absence of the variant ‘T’ allele. In White control subjects the frequency of the ‘T’ allele was 0.092, with T/T, C/T and C/C genotype frequencies of 0.00, 0.183, and 0.817, respectively. CONCLUSION: This study shows that the rs2476601 SNP of the PTPN22 gene is nonpolymorphic in BSA and therefore not associated with RA but the minor ‘T’ allele frequency in White South Africans is similar to that in other European populations. However, since variations in the rest of the gene were not investigated, these results do not exclude other PTPN22 polymorphisms from playing a role in RA susceptibility in BSA.

Bismuth(III) has been used in the medicinal industry for many years, but its mechanism of action is not fully understood and there is very little information on thermodynamic and kinetic parameters for complex formation. Amino acids are the building blocks of life and so, by initially simply determining the complexing ability of various amino acids with bismuth, an indication of how bismuth could interact in the body can slowly be developed and could assist in the eventual development and design of more effective bismuth containing drugs.

Thesis advisor: Abhishek Chatterjee / Noncanonical amino acid (ncAA) mutagenesis provides powerful new ways to probe and manipulate protein function both in vitro and in living cells. Increasing the number of ncAAs that can be site-specifically encoded can greatly expand the scope of this promising technology. We aimed to address the challenges that limit the multisite ncAA incorporation technology in both Escherichia coli and mammalian cells. Our work has significantly expanded the scope of this technology through the development of mutually compatible suppression systems and the optimization of their expression. Using these platforms, we further demonstrate powerful new applications of dual-ncAA incorporation technology both in E. coli and mammalian cells. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

In this dissertation, we discuss the development of a synthetic method to functionalize various α-haloglycine esters, as key precursors to a large variety of non-proteinogenic α-amino acids (Xaas). At first, we discovered a very practical and high yielding acetyl chloride-mediated cascade reaction to synthesize α-arylated amino esters in one-pot. In this multicomponent reaction (MCR), a primary carbamate was condensed with a glyoxylate, followed by an in situ halogenation which proved essential to trigger the final Friedel−Crafts functionalization. After careful reaction optimization, a plethora of arene nucleophiles were reacted with high regioselectively in CHCl3 at low temperatures (Method A) while less activated arenes reacted more cleanly in CH3CN and at higher temperatures (Method B). To broaden the scope of this reaction to acid sensitive nucleophiles, a one-pot reaction was designed via evaporation of all acid by-products at the α-haloglycine stage. The anion-binding Schreiner’s thiourea catalyst proved to be extremely efficient to promote this complementary approach (Method C) which relies on the chloride leaving group activation by the catalyst to assist the functionalization stage and deliver the α-amino ester product. In the second chapter, some highly practical and efficient preparations of α-haloglycine esters in one-pot have been developed to generate useful precursors of non-proteinogenic α-amino esters. Also, a mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation/deoxy halogenation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. Friedel–Crafts reaction between α-chloroglycine and N-methylindole have been studied in details to understand the mechanistic intricacy of this reaction. Our findings through the initial kinetic profiling support that the arylation likely proceeds via a SN1-like (or SN2C+) mechanism. In third chapter, we discuss the development of the most challenging α,α-disubstituted amino esters in a multicomponent fashion. Our results highlight that the MCR proceeds via the formation of an enamide intermediate, which is further tautomerized to corresponding iminium to produce the desired product. In collaboration with Eli Lilly at the Automated Synthesis Laboratory (ASL), we have developed silver (I) salts mediated Friedel–Crafts reaction for synthesis of α-trifluoromethylated α-amino esters on a fully automatized robot. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection