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Master of Science / Department of Food Science / J. Scott Smith / Heterocyclic amines (HCAs) formed during cooking of meats at high temperatures are suspected cancer causing compounds and efforts have been made to reduce their levels. Spices possessing high levels of antioxidants have been shown to inhibit these compounds when incorporated prior to cooking. Seven spices, black pepper, rosemary, turmeric, thyme, cinnamon, ginger and oregano were analyzed for their antioxidant capacity using three different assays. These spices were individually added at 0.25% to beef patties fried at 400 °F for 5 min per side to evaluate their effect on HCA inhibition. Black pepper was emphasized in this study by studying the effect of addition at different concentrations (0.25, 0.50, 1.00 %) on HCA reduction. It was found that patties treated with black pepper individually, as well in combination with other spices, greatly decreased the formation of HCAs. Black pepper at 0.25% level showed the highest inhibition of PhIP levels (85%). The spices were shown to have high levels of free radical scavenging activity as measured by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Overall, black pepper had significantly lower DPPH scavenging activity but still showed high HCA inhibition. All the spices individually inhibited HCA by 55-82%. Black pepper in combination with turmeric was the best combination, showing a 94.74% inhibition of HCA formation.

Call number: LD2668 .T4 1984 V47 / Master of Science

Master of Science / Food Science Institute / J. Scott Smith / Heterocyclic amines (HCAs) are a class of toxicological compounds that can be formed during heating of precursors, amino acids, creatinine, creatine, and sugars at high temperature cooking of muscle products. These potent mutagens are suspected to play a role in human cancers. The objective of this study was to investigate a practical method to reduce the amount of HCAs through marinating of beef steaks. We were interested in the potential health benefits of natural extracts containing polyphenols present in commercial marinades. HCAs were compared in marinated and unmarinated steaks. Four common HCAs were investigated: 2-amino-3,8- dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenyl-imidazo[4,5- b]pyridine (PhIP), 1-methyl-9H-pyrido[4,3-b]-indol (harman), and 9H-pyrido[4,3-b]-indol (norharman). Steaks were marinated for one hour and grilled at 400 °F for 5 minutes at each side. Meat samples were extracted by solid phase extraction (SPE) and analysis with HPLC showed the significant decrease (p < 0.05) of sum of polar and nonpolar HCAs by 71% compared to untreated steaks. For confirmation of spices potency on reduction of HCA formation, the same experiment was applied to meat with the base of commercial marinade powders excluding the herbs and spices. Lesser reduction of HCAs were shown and in some cases no significant reduction occurred. HPLC analysis showed presence of considerable amount of natural phenolic antioxidants of carnosic acid, carnosol, and rosmarinic acid, which can be related to the reduction effects of HCA formation in commercial marinades. These results revealed that marinating meats before grilling with various spices/herbs containing antioxidants may reduce formation of mutagenic /carcinogenic HCAs markedly.

Salt formation provides a means of altering the physicochemical and resultant biological characteristics of a drug entity without modifying its molecular structure. Many published reviews have indicated the importance of the selection of the most appropriate salt form. This work is an investigation into the salt formation of two heterocyclic drugs. This is done by the physicochemical and the crystallographic studies of 19 high resolution single crystal diffraction studies. The particular targets of the work are the selection of the most appropriate salt forms, investigations into the tautomerism and polymorphism (or pseudopolymorphism) and an understanding of the interactions most likely between these heterocyclic drugs and their specific receptor sites. Section 1 describes the effect of protonation on the absorption of drugs, the rationale for using various salt forms and the resultant effect this has on a number of physicochemical properties of the parent compound. Section 2 is a description of the experimental techniques used in the physicochemical investigations and in crystal structure determination. In Sections 3 and 7, the preparation and characterisation of the salts and modifications of the two heterocyclic drugs, GU and IM is described. In Sections 4 and 8, the physicochemical investigations into the hygroscopicity and solid-state stabilities of the salts of GU and IM is described. Van't Hoff solubility studies are used to determine the enthalpies of solution and where appropriate the relative thermodynamic stabilities of the various phases produced. The structures of 19 of the salts or modifications of GU and IM, together with their packing and hydrogen bonding interactions is described in Sections 5 and 9. Sections 6 and 10 describe the ionisation properties of these molecules. Both the guanidine and imidazole moieties of GU and IM, respectively, are tautomeric, the particular form(s) found in these investigations and the effect of protonation is discussed. The conformations of these structures are discussed and the effect of protonation, especially on the puckering of the piperazine ring, is described.

A novel class of potential positron emission tomography (PET) radiotracers for imaging aminopeptidase N (also known as APN or CD13) and cannabinoid type 1 (CB1) receptors were designed and synthesised with an efficient chemical strategy. Both targets have remarkable diagnostic and therapeutic potential, in fact the CD13 receptors are over-expressed during tumour angiogenesis and the CB1 receptors are highly expressed in the brain playing important functions in several pathophysiological processes. The target compounds were obtained by means of oxime-bio-conjugation between fluoro-deoxy-carbohydrates, used as prosthetic groups, and hydroxylamine-functionalised cyclic NGR (asparagine-glycine-arginine) motif sequences for CD13 receptor and rimonabant-type pyrazoles for the CB1 receptor. In particular, aminooxy-cyclic NGR peptides were conjugated with the novel prosthetic group 5-FDR (5-fluoro-5-deoxy-D-ribose) and the aminooxy- pyrazole-type cannabinoid molecules were conjugated with both 5-FDR and with FDG (2-fluoro-2-deoxy-D-glucose). 5-FDR proved to be superior to FDG, as the bioconjugation reaction occurred in milder conditions (room temperature vs 100 °C) and at faster rate. Furthermore, we observed that the rate of the oxime bond formation depends on the solubility of the aminooxy-functionalized core used. In fact, the bioconjugation with hydrophilic cyclic aminooxy-NGR peptides was faster than in the case of lipophilic aminooxy-pyrazoles (10 min vs 20-30 min). The receptor affinity is decreased in the case of the CB1 receptors after conjugation with the fluoro-carbohydrates. This is not observed with the conjugated NGR peptides, which maintain similar affinity for the CD13 receptor compared with the unconjugated NGR. In conclusion, we have developed an efficient strategy for the synthesis of a novel class of CD13 ligands, which may be also produced in radiofluorinated form, and explored a novel bioconjugation strategy for CB1 receptor ligands. Both may have important applications in the development of PET tracers.