ABSTRACT
Advanced Glycation Endproducts (AGEs) are modified amino acids that form on proteins and are known to be implicated in the pathogenesis of diabetes and related diseases. Ready access to synthetic stable isotope-labelled AGEs allows for quantitative mass spectrometry studies to be undertaken, providing key insights into the roles AGEs play in the progression of such diseases. However, the majority of current syntheses of these compounds suffer from poor yields and lengthy procedures and are not suitable for the purposes required here. Here, we report robust syntheses of stable isotope-labelled monolysyl AGEs, N(ε)-(carboxymethyl)lysine, N(ε)-(carboxyethyl)lysine and pyrraline, that provide straightforward access to these compounds for quantitative amino acid analysis. This work will facilitate future investigations with these compounds and lead to a better understanding of the roles they play in diabetes and related diseases.
Subject(s)
Glycation End Products, Advanced/chemical synthesis , Isotope Labeling/methods , Lysine/analogs & derivatives , Norleucine/analogs & derivatives , Pyrroles/chemical synthesis , Diabetes Mellitus/metabolism , Lysine/chemical synthesis , Mass Spectrometry , Norleucine/chemical synthesisABSTRACT
By using the Telospot assay, 27 different extracts of cyanobacteria were evaluated for telomerase inhibition. All extracts showed varying, but significant activity. We selected Microcystis aeruguinosa PCC 7806 to identify the active compound and a bioassay guided fractionation led us to isolate mixtures of sulfoquinovosyl diacylglycerols (SQDGs), which were identified by 2D NMR and MS/MS experiments. Pure SQDG derivatives were then synthesized. The IC(50) values of pure synthetic sulfoquinovosyl dipalmitoylglycerol and the monopalmitoylated derivative against telomerase were determined to be 17 and 40 µM, respectively. A structure-activity relationship study allowed the identification of compounds with modified lipophilic acyl groups that display improved activity.
Subject(s)
Diglycerides/chemical synthesis , Glycolipids/chemical synthesis , Microcystis/metabolism , Telomerase/antagonists & inhibitors , Diglycerides/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycolipids/chemistry , Phencyclidine/analogs & derivatives , Structure-Activity Relationship , Tandem Mass Spectrometry , Telomerase/metabolismABSTRACT
The synthesis of advanced glycation endproducts (AGEs), CML, CEL, and pyrraline and their incorporation into collagen model peptides is reported. AGEs are modified amino acids that form on proteins such as collagen and are thought to play a significant role in the pathogenesis of many diseases, particularly diabetes. The synthesis and incorporation of these compounds into synthetic peptides is a key step in developing model systems with which to investigate AGE-modified proteins.
Subject(s)
Glycation End Products, Advanced/chemical synthesis , Models, Molecular , Amino Acids/chemistry , Collagen/chemistry , Glycation End Products, Advanced/chemistry , Glycosylation , Molecular Structure , Peptides/chemistry , Pyrroles/chemistrySubject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Withanolides/chemical synthesis , Amyloid Precursor Protein Secretases/metabolism , Cell Differentiation/drug effects , Cell Line, Tumor , Crystallography, X-Ray , Humans , Molecular Conformation , Neurites/drug effects , Neurites/physiology , Singlet Oxygen/chemistry , Stereoisomerism , Withania/chemistry , Withanolides/chemistry , Withanolides/pharmacologyABSTRACT
This review describes the design, synthesis and evaluation of novel catechol based anchors for surface modification. The anachelin chromophore, the catecholate fragment of the siderophore anachelin from the cyanobacterium Anabaena cylindrica, allows for the immobilization of polyethylene glycol (PEG) on titania and glass surfaces thus rendering them protein resistant and antifouling. It is proposed that catecholate siderophores constitute a class of natural products useful for surface modification similar to dihydroxyphenylalanine and dopamine derived compounds found in mussel adhesive proteins. Second-generation dopamine derivatives featuring a quaternary ammonium group were found to be equally efficient in generating antifouling surfaces. The anachelin chromophore, merged via a PEG linker to the glycopeptide antibiotic vancomycin, allowed for the generation of antimicrobial surfaces through an operationally simple dip-and-rinse procedure. This approach offers an option for the prevention of nosocomial infections through antimicrobial implants, catheters and stents. Consequences for the mild generation of functional biomaterials are discussed and novel strategies for the immobilization of complex natural products, proteins and DNA on surfaces are presented.
Subject(s)
Biocompatible Materials/chemistry , Cyanobacteria/metabolism , Quinolinium Compounds/chemistry , Siderophores/chemistry , Biocompatible Materials/chemical synthesis , Molecular StructureABSTRACT
The use of enol phosphinates as electrophiles for cross-coupling reactions has been explored. Both boronic acids (Suzuki-Miyaura reaction) and stannanes (Stille reaction) couple efficiently with lactam derived phosphinates.
Subject(s)
Cross-Linking Reagents/chemistry , Phosphinic Acids/chemistry , Catalysis , Lactams/chemistry , Transition Elements/chemistryABSTRACT
ortho-Lithiation of cyclic aryl sulfonamides in the presence of phosphoryl chloride provides a very simple entry to fused polycyclic sultams (benzothiazolines and naphthathiazolines).
