AURONE-DERIVED TRIAZOLES AS POTENTIAL SCAFFOLDS FOR FLUORESCENT AND ANTI-INFLAMMATORY MOLECULES

Abstract

Natural products derived from various plants have been used throughout history for many different purposes. One such naturally occurring compound, flavonoids, are responsible for the pigmentation in most flowering plants. Flavonoids have been demonstrated to have unique properties, both biological and photophysical. Various classes of flavonoids exist including flavones and flavonols, which have been studied for their biological activities. Two flavonoids, Quercetin and Apigenin, are commercially available and have been shown to possess anti-inflammatory properties. One derivative of flavone, the aurone, has been predominantly examined for their photophysical properties as fluorophores and their biological activities in cancer cells. Recently, studies have implicated aurones as anti-inflammatories, though their mechanism has yet to be thoroughly elucidated. Aurones are highly modifiable, and many substitutions can be added to either the benzofuranone or benzylidene groups, or both, thus modulating their biological activities and fluorescent properties. Compounds containing the 1,2,3-triazole moiety have been explored for their use as COX-2 inhibitors and as fluorophores. Therefore, it was thought that the incorporation of a 1,2,3-triazole as a modification of existing aurones may lead to similar, if not more potent fluorescent and biological activities. This dissertation explores the use of novel aurone-derived salicyl-substituted 1,2,3-triazoles (ATs) as fluorescence molecules and anti-inflammatory compounds. It was found that, with the appropriate modifications, certain ATs may exhibit such properties. A single representative AT was utilized for each purpose. AT5 was shown to have unique properties as a fluorophore, yielding an excitation and emission spectra with a large Stokes shift, which increased as polarity of the solvent increased and was maximal in phosphate buffered saline, while also increased in other aqueous or protic solutions. Another AT, AT111, was demonstrated to have anti-inflammatory properties, limiting the effect of LPS on the induction of an inflammatory response in macrophages. AT111 lowered the production of inflammatory mediators such as IL-6, MCP-1, and iNOS, while not interfering with expression of other inflammatory proteins such as TNF-α and COX-2. It was determined that AT111 did not mitigate the initial TLR4 driven NF-κB response but did increase phosphorylation of ERK2. AT111 was also shown to increase histone, TRAF4, and MKNK2 transcription in both PMA-differentiated U937 human and RAW 264.7 murine macrophage-like cells. Gene expression profiles, along with the modulation of LPS-induced expression of many inflammatory proteins, but not all attributed to LPS, possibly implicates various mechanisms that are different from those observed in many anti-inflammatory compounds. Though the aforementioned effects were only apparent in the higher micromolar range, this dissertation demonstrates the potential for these novel ATs to function as both a fluorescent and anti-inflammatory scaffold that may be modified to augment these effects.