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

Abstract

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.

Figure 1

CEP induces activation of the NLRP3 inflammasome in bone marrow derived macrophages.

Figure 2

Bevacizumab and anti-CEP antibodies have complementary antiangiogenic activities both of which lead to hypoxia-induced inflammation. iNOS promotes lipid oxidation and the generation of more CEP. HIF-1 promotes expression of VEGF and TLR2. Activation of TLR2 or TLR9 by CEP fosters an invasive phenotype, which is associated with bevcizumab failure, by promoting MMP expression/activation by GAM, GSC, CAF and GBM cells.

Scheme 1

Oxidative fragmentation of linoleyl and docosahexaenoyl phospholipids produces γ-hydroxyalkenals that react with protein lysyl residues to deliver pyrrole derivatives.

Scheme 2

Spontaneous deacylation of HOHA phospholipids, e.g., HOHA-PC, generates HOHA-lactone that reacts with proteins to generate CEP derivatives.