ABSTRACT
Cyclic pyranopterin monophosphate (1), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of 1 hydrobromide (1·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and D-galactose phenylhydrazone to give the pyranopterin (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one (10) and establishing all four stereocenters found in 1. Compound 10, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-tert-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (15). The latter underwent a Swern oxidation and then deprotection to give 1·HBr. Synthesized 1·HBr had in vitro efficacy comparable to that of 1 of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase-molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up.
Subject(s)
Coenzymes/chemistry , Metalloproteins/chemistry , Organophosphorus Compounds/chemical synthesis , Pteridines/chemistry , Pterins/chemical synthesis , Coenzymes/metabolism , Escherichia coli/metabolism , Humans , Metalloproteins/metabolism , Molybdenum Cofactors , Organophosphorus Compounds/chemistry , Pteridines/metabolism , Pterins/chemistry , Signal Transduction , StereoisomerismABSTRACT
A series of eight novel, highly modified mono-, di- and trisaccharide derivatives, each containing an iminoalditol moiety, has been synthesized in the quest for potential heparanase inhibitors.
Subject(s)
Aza Compounds/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucuronidase/antagonists & inhibitors , Heparitin Sulfate/chemical synthesis , Heparitin Sulfate/pharmacology , Enzyme Inhibitors/chemistry , Heparitin Sulfate/analogs & derivatives , Heparitin Sulfate/chemistry , HumansABSTRACT
4-Nitrophenyl [sodium beta-D-glucopyranosyluronate]-(1-->3)-2-acetamido-2-deoxy-beta-D-glucopyranoside (1) and 4-nitrophenyl [sodium beta-D-glucopyranosyluronate]-(1-->3)-2-acetamido-2-deoxy-beta-D-galactopyranoside (2) were prepared from the zwitterions hyalobiuronic acid [beta-D-glucopyranuronic acid-(1-->3)-2-amino-2-deoxy-D-glucopyranose] and chondrosine [beta-D-glucopyranuronic acid-(1-->3)-2-amino-2-deoxy-D-galactopyranose], respectively. Compounds 1 and 2 were not hydrolysed by bovine testicular hyaluronidase.
