title: Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway.
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.
authors: Carbohydrate Chemistry Team, Callaghan Innovation, P.O. Box 31-310, Lower Hutt 5040, New Zealand. keith.clinch@callaghaninnovation.govt.nz
authors: Keith
authors: K
authors: Clinch
authors: Derek K
authors: DK
authors: Watt
authors: Rachel A
authors: RA
authors: Dixon
authors: Sylvia M
authors: SM
authors: Baars
authors: Graeme J
authors: GJ
authors: Gainsford
authors: Ashish
authors: A
authors: Tiwari
authors: Günter
authors: G
authors: Schwarz
authors: Yas
authors: Y
authors: Saotome
authors: Michael
authors: M
authors: Storek
authors: Abdel A
authors: AA
authors: Belaidi
authors: Jose A
authors: JA
authors: Santamaria-Araujo
mesh_terms: D003067:Coenzymes / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D008667:Metalloproteins / Q000737:chemistry* / Q000378:metabolism; D000090006:Molybdenum Cofactors; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D011621:Pteridines / Q000737:chemistry* / Q000378:metabolism; D011622:Pterins / Q000138:chemical synthesis* / Q000737:chemistry; D015398:Signal Transduction; D013237:Stereoisomerism
chemical_list: D003067:Coenzymes; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D009943:Organophosphorus Compounds; D011621:Pteridines; D011622:Pterins; C549445:nulibry; C022261:molybdopterin