Z-D-norleucine

Cardiovascular diseases (CVDs) are the leading cause of death globally. While the major focus of pharmacological and non-pharmacological interventions has been on targeting disease pathophysiology and limiting predisposing factors, our understanding of the cellular and molecular mechanisms underlying the pathogenesis of CVDs remains incomplete. One mechanism that has recently emerged is protein O-GlcNAcylation. This is a dynamic, site-specific reversible post-translational modification of serine and threonine residues on target proteins and is controlled by two enzymes: O-linked β-N-acetylglucosamine transferase (OGT) and O-linked β-N-acetylglucosaminidase (OGA). Protein O-GlcNAcylation alters the cellular functions of these target proteins which play vital roles in pathways that modulate vascular homeostasis and cardiac function. Through this review, we aim to give insights on the role of protein O-GlcNAcylation in cardiovascular diseases and identify potential therapeutic targets in this pathway for development of more effective medicines to improve patient outcomes.

Introduction: Senescence of peritoneal mesothelial cells represents a biological program defined by arrested cell growth and altered cell secretory phenotype with potential impact in peritoneal dialysis. This study aims to characterize cellular senescence at the level of global protein expression profiles and modification of proteins with O-linked N-acetylglucosamine (O-GlcNAcylation). Methods: A comparative proteomics analysis between young and senescent human peritoneal mesothelial cells (HPMC) was performed using two-dimensional gel electrophoresis. O-GlcNAc status was assessed by Western blot under normal conditions and after modulation with 6-diazo-5-oxo-L-norleucine (DON) to decrease O-GlcNAcylation or O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenyl carbamate (PUGNAc) to increase O-GlcNAcylation. Results: Comparison of protein pattern of senescent and young HPMC revealed 29 differentially abundant protein spots, 11 of which were identified to be actin (cytoplasmic 1 and 2), cytokeratin-7, cofilin-2, transgelin-2, Hsp60, Hsc70, proteasome β-subunits (type-2 and type-3), nucleoside diphosphate kinase A, and cytosolic 5'(3')-deoxyribonucleotidase. Although the global level of O-GlcNAcylation was comparable, senescent cells were not sensitive to modulation by PUGNAc. Discussion: This study identified changes of the proteome and altered dynamics of O-GlcNAc regulation in senescent mesothelial cells. Whereas changes in cytoskeleton-associated proteins likely reflect altered cell morphology, changes in chaperoning and housekeeping proteins may have functional impact on cellular stress response in peritoneal dialysis.

We report the synthesis of carbazole-based unnatural α-amino acid and non-α-amino acid derivatives via a Pd(II)-catalyzed bidentate directing group 8-aminoquinoline-aided β-C(sp3)-H activation/functionalization method. Various N-phthaloyl, DL-, L- and D-carboxamides derived from their corresponding α-amino acids, non-α-amino acids and aliphatic carboxamides were subjected to the β-C(sp3)-H functionalization with 3-iodocarbazoles in the presence of a Pd(II) catalyst to afford the corresponding carbazole moiety installed unnatural amino acid derivatives and aliphatic carboxamides. Carbazole motif-containing racemic (DL) and enantiopure (L and D) amino acid derivatives including phenylalanine, norvaline, leucine, norleucine and 2-aminooctanoic acid with anti-stereochemistry and various non-α-amino acid derivatives including GABA have been synthesized. Removal of the 8-aminoquinoline directing group, deprotection of the phthalimide moiety and the preparation of carbazole amino acid derivatives containing free amino- and carboxylate groups are shown. The carbazole motif is prevalent in alkaloids and biologically active molecules and functional materials. Thus, this work on the synthesis of carbazole-based unnatural amino acid derivatives would enrich the libraries of unnatural amino acid derivatives and carbazoles.