Carboxyethylpyrroles: From Hypothesis to the Discovery of Biologically Active Natural Products.

Our research on the roles of lipid oxidation in human disease is guided by chemical intuition. For example, we postulated that 2-(ω-carboxyethyl)pyrrole (CEP) derivatives of primary amines would be produced through covalent adduction of a γ-hydroxyalkenal generated, in turn, through oxidative fragmentation of docosahexaenoates. Our studies confirmed the natural occurrence of this chemistry, and the biological activities of these natural products and their extensive involvements in human physiology (wound healing) and pathology (age-related macular degeneration, autism, atherosclerosis, sickle cell disease, and tumor growth) continue to emerge. This perspective recounts these discoveries and proposes new frontiers where further developments are likely. Perhaps more significantly, it depicts an effective chemistry-based approach to the discovery of novel biochemistry.