The Discovery, Synthesis, and Characterization of Biological Signaling Molecules and Signaling Disruptors

Chemical biology is a multidisciplinary field, combining perspectives and techniques from biology and chemistry to study biological systems. Often, these multidisciplinary endeavors hinge on the application of the powerful tools of synthetic and analytical chemistry to solve problems or test an interesting hypothesis in a biological system. The viewpoint of biology offers a larger scope with the potential for more immediately applicable results. Application of organic synthesis and analytical techniques identify biological signals or signal disrupters. Following, perturbation of a signaling pathway via a synthetic signaling molecule modulates the transcription of a desired gene produced correlated to a phenotype of interest or aids in the identification of an unknown component in the biological degradation of a chemical signal. Finally, implementation of nuclear magnetic resonance (NMR) and/or high performance liquid chromatography- mass spectrometry (HPLC-MS) contributes to elucidating the structure, annotating the identity, or quantitating biological signals or signal disrupters. In the first study, a library of 1-(4-substitutedphenyl)pyrazole-based glucocorticoid (GC) analogues were synthesized and evaluated for their ability to reduce inflammation with a reduced impact on insulin production. Compounds 11aa and 11ab at 1 μM [micromolar] reduced inflammation to a similar extent to dexamethasone 10 nM with improved transactivation and reduced impact on insulin production. In the process of screening, structure-activity relationships were also shown to be correlated to the desired biological activity. In the second series of studies, 4-methylphenol (4MP), a putative anoxic, abiotic, mineral-mediated degradation product of bisphenol A (BPA), was shown to not be a BPA degradation product. Additionally, it was shown that BPA is not inert under anoxic conditions and that MnO₂ [magnesium oxide]-mediated coupled abiotic−biotic processes may be relevant for controlling the fate and longevity of BPA in sediments and aquifers. In the third study, the N-acyl homoserine lactone (AHL) production, gene transcription, and phenotype expression of Phaeobacter sp. strain Y4I was quantitated to ultimately describe the regulation of indigoidine biosynthesis by two quorum sensing gene sequences. In the fourth study, AHLs are shown to be present in coral black band disease (BBD) and their production, enhanced by temperature, may control the structuring of infected and healthy coral microbial communities.