Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in Caenorhabditis elegans.

The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food ubiquitously, from the baking industry to our everyday lives. However, the Maillard reaction also occurs in all cells, from prokaryotes to eukaryotes, forming advanced glycation end-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNAseq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGE (MG-H1)-induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream regulator for increased feeding upon accumulation of AGEs by partially controlling the expression of tdc-1 gene. Furthermore, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MG-H1 AGE. Understanding this signaling pathway may help understand hedonistic overfeeding behavior observed due to modern AGE-rich diets.

Sequential Norrish-Yang Cyclization and C-C Cleavage/Cross-Coupling of a [4.1.0] Fused Saturated Azacycle.

Methods that functionalize the periphery of azacylic scaffolds have garnered increasing interest in recent years. Herein, we investigate the selectivity of a solid-state Norrish-Yang cyclization (NYC) and subsequent C-C cleavage/cross-coupling reaction of a strained cyclopropane-fused azacyclic system. Surprisingly, the NYC primarily furnished a single lactam constitutional and diastereo-isomer. The regioselectivity of the C-C cleavage of the α-hydroxy-ß-lactam moiety could be varied by altering the ligand set used in the coupling chemistry. Experimental and computational observations are discussed.

C─C Cleavage Approach to C─H Functionalization of Saturated Aza-Cycles.

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α-hydroxy-ß-lactams under mild, visible light conditions using a Norrish-Yang process to affect α-functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C─H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted opening of the N-fused bicyclo α-hydroxy-ß-lactams. Computational studies have provided insight into the origin of the complementary C─C cleavage processes.