ABSTRACT
Resolvins are family of lipid mediators derived from omega-3 polyunsaturated fatty acids, which are generated during the resolution phase of acute inflammation. Resolvin E1 is biosynthesized from eicosapentaenoic acid via 18(R)-hydroxyeicosapentaenoic acid (18R-HEPE) in the Cox-2 and lipoxygenase mediated pathway and has proven to exhibit potent anti-inflammatory activity. We report herein the first total chemical synthesis of 18R-HEPE and demonstrate that this compound displays in vivo bioactivity by blocking neutrophil infiltration in a murine model of zymosan-induced peritonitis.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Eicosapentaenoic Acid/analogs & derivatives , Peritonitis/drug therapy , Animals , Anti-Inflammatory Agents/chemistry , Disease Models, Animal , Eicosapentaenoic Acid/chemical synthesis , Eicosapentaenoic Acid/chemistry , Eicosapentaenoic Acid/pharmacology , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Neutrophil Infiltration/drug effects , Peritonitis/chemically induced , Stereoisomerism , ZymosanABSTRACT
Selectins (L, E, and P) are vascular endothelial molecules that play an important role in the recruitment of leukocytes to inflamed tissue. In this regard, P-Selectin glycoprotein-1 (PSGL-1) has been identified as a ligand for P-Selectin. PSGL-1 binds to P-Selectin through the interaction of core-2 O-glycan expressing sialyl Lewis(x) oligosaccharide and the three tyrosine sulfate residues. Herein, we report the synthesis of threonine-linked core-2 O-glycan as an amino acid building block for the synthesis of PSGL-1. This building block was further incorporated in the Fmoc-assisted solid-phase peptide synthesis to provide a portion of the PSGL-1 glycopeptide.
Subject(s)
Fluorenes/chemistry , Membrane Glycoproteins/chemistry , Peptide Fragments/chemistry , Peptide Fragments/chemical synthesis , Polysaccharides/chemistry , Polysaccharides/chemical synthesis , Threonine/chemistry , Carbohydrate Sequence , Catalysis , Molecular Sequence DataABSTRACT
[structure: see text] A family of cyclic 1-deoxysphingolipid derivatives of structure 4 has been designed and synthesized, which may serve as tumorigenesis suppressors for various cancers. Compound 4 is a second-generation analogue developed from sphingosine (1), in which a hydroxyl substituent is moved from C1 to C5 and a methylene is added for conformational rigidity between the C2-nitrogen substituent and C4. The synthetic chemistry for pyrrolidine ring closure at C3-C4 features ring-closing metathesis followed by hydroboration-oxidation.
Subject(s)
Pyrrolidines/chemistry , Pyrrolidines/chemical synthesis , Sphingosine/analogs & derivatives , Cyclization , Molecular Structure , Sphingosine/chemical synthesis , Sphingosine/chemistry , StereoisomerismABSTRACT
Six lignans, including the cyclolignan 3,4'-dihydroxy-3',4'-dimethoxy-6,7'-cyclolignan, were isolated from the flowering tops of Larrea tridentata. Additionally the flavanone, (S)-4',5-dihydroxy-7-methoxyflavanone, was isolated for the first time from L. tridentata or any member of the family Zygophyllaceae. All of the compounds were assessed for their growth inhibitory activity against human breast cancer, human colon cancer and human melanoma cell lines. The lignans had IC50 values of 5-60 microM with the linear butane-type lignans being the most potent, and it was found that colon cancer cells were the least sensitive cell type tested. The relative potency of linear butane type lignans against human breast cancer appears to correlate positively with the number of O-methyl groups present on the molecule.