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1.
Bioconjug Chem ; 30(3): 785-792, 2019 03 20.
Article in English | MEDLINE | ID: mdl-30629410

ABSTRACT

Cholera is a potentially fatal bacterial infection that affects a large number of people in developing countries. It is caused by the cholera toxin (CT), an AB5 toxin secreted by Vibrio cholera. The toxin comprises a toxic A-subunit and a pentameric B-subunit that bind to the intestinal cell surface. Several monovalent and multivalent inhibitors of the toxin have been synthesized but are too complicated and expensive for practical use in developing countries. Meta-nitrophenyl α-galactoside (MNPG) is a known promising ligand for CT, and here mono- and multivalent compounds based on MNPG were synthesized. We present the synthesis of MNPG in greatly improved yields and its use while linked to a multivalent scaffold. We used economical polymers as multivalent scaffolds, namely, polyacrylamide, dextran, and hyperbranched polyglycerols (hPGs). Copper-catalyzed alkyne azide cycloaddition reaction (CuAAC) produced the inhibitors that were tested in an ELISA-type assay and an intestinal organoid swelling inhibition assay. The inhibitory properties varied widely depending on the type of polymer, and the most potent conjugates showed IC50 values in the nanomolar range.


Subject(s)
Cholera Toxin/antagonists & inhibitors , Galactosides/metabolism , Polymers/pharmacology , Cholera Toxin/metabolism , Enzyme-Linked Immunosorbent Assay , Ligands , Vibrio cholerae/metabolism
2.
ChemMedChem ; 12(7): 483-486, 2017 04 06.
Article in English | MEDLINE | ID: mdl-28328014

ABSTRACT

A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant ß-glucocerebrosidase with IC50 values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for ß-galactosidase from bovine liver. No inhibition of human recombinant ß-glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA).


Subject(s)
Enzyme Inhibitors/chemistry , Glucosylceramidase/antagonists & inhibitors , Guanidine/chemistry , Xylitol/chemistry , Animals , Binding Sites , Cattle , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Glucosylceramidase/genetics , Glucosylceramidase/metabolism , Humans , Liver/enzymology , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Structure-Activity Relationship , Xylitol/chemical synthesis , Xylitol/metabolism , beta-Galactosidase/antagonists & inhibitors , beta-Galactosidase/metabolism
3.
Org Biomol Chem ; 13(2): 549-60, 2015 Jan 14.
Article in English | MEDLINE | ID: mdl-25380215

ABSTRACT

The protein arginine N-methyltransferases (PRMTs) are a family of enzymes that function by specifically transferring a methyl group from the cofactor S-adenosyl-L-methionine (AdoMet) to the guanidine group of arginine residues in target proteins. The most notable is the PRMT-mediated methylation of arginine residues that are present in histone proteins which can lead to chromatin remodelling and influence gene transcription. A growing body of evidence now implicates dysregulated PRMT activity in a number of diseases including various forms of cancer. The development of PRMT inhibitors may therefore hold potential as a means of developing new therapeutics. We here report the synthesis and evaluation of a series of small molecule PRMT inhibitors designed to simultaneously occupy the binding sites of both the guanidino substrate and AdoMet cofactor. Potent inhibition and surprising selectivity were observed when testing these compounds against a panel of methyltransferases.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Binding Sites , Enzyme Inhibitors/metabolism , Magnetic Resonance Spectroscopy , Protein-Arginine N-Methyltransferases/metabolism , Spectrometry, Mass, Electrospray Ionization
4.
Bioorg Med Chem ; 21(2): 553-9, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23238078

ABSTRACT

Incorporation of the unnatural amino acid L-(7-hydroxycoumarin-4-yl)ethylglycine (7-HC) is a powerful and reliable approach for the preparation of fluorescently labeled proteins. The growing popularity of this valuable amino acid prompted us to pursue an improved protocol for its synthetic preparation. The optimized procedure here described provides ready access to multi-gram quantities of 7-HC. Also reported is an extension of the utility of 7-HC in the generation of a protected building block suitable for use in solid phase peptide synthesis. The building block was successfully incorporated at various positions in a series of model peptides, including analogues of the cell penetrating HIV-Tat peptide, further illustrating the utility of this unique amino acid.


Subject(s)
Glycine/analogs & derivatives , Peptides/chemical synthesis , Umbelliferones/chemistry , Amino Acid Sequence , Glycine/chemistry , HIV-1/metabolism , HeLa Cells , Humans , Hydrogen-Ion Concentration , Microscopy, Confocal , Peptide Fragments/chemistry , Peptides/chemistry , Peptides/metabolism , Solid-Phase Synthesis Techniques , tat Gene Products, Human Immunodeficiency Virus/chemistry
5.
Phytochemistry ; 62(8): 1225-9, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12648541

ABSTRACT

The seed of Cedrelopsis grevei (Ptaeroxylaceae) has yielded the known compounds uvangoletin, 5,7-dimethylpinocembrin, cardamonin, flavokawin B, 2'-methoxyhelikrausichalcone, and the novel prenylated chalcones, cedreprenone and cedrediprenone. Cedridiprenone has been shown to exhibit superoxide scavenging properties.


Subject(s)
Chalcone/chemistry , Chalcone/isolation & purification , Meliaceae/chemistry , Seeds/chemistry , Chromatography, Gel/methods , Fruit/chemistry , Nuclear Magnetic Resonance, Biomolecular , Spectrometry, Mass, Electrospray Ionization
6.
Phytochemistry ; 61(8): 919-22, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12453517

ABSTRACT

The stem bark of Cedrelopsis grevei Baill. has yielded the first reported examples of 5-prenylated coumarins, cedrecoumarin A and B as well as the known coumarins, cedrelopsin, scoparone, O-methylcedrelopsin and norbraylin, and the known chromones ptaeroglycol and ptaeroxylinol.


Subject(s)
Coumarins/chemistry , Coumarins/isolation & purification , Meliaceae/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure
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