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TitleSynthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway
Publication TypeJournal Article
Year of Publication2013
AuthorsClinch, K., Watt D.K., Dixon R.A., Baars S.M., Gainsford G.J., Tiwari A., Schwarz G., Saotome Y., Storek M., Belaidi A.A., and Santamaria-Araujo J.A.
JournalJournal of Medicinal Chemistry
Pagination1730 - 1738
Date Published2013
ISSN00222623 (ISSN)
KeywordsAmadori rearrangement, article, bacterium culture, biological activity, Coenzymes, Crystallization, cyclization, diastereoisomer, Escherichia coli, human, Humans, in vitro study, Metalloproteins, molybdenum, nonhuman, Organophosphorus Compounds, Pteridines, Pterins, pyranopterin monophosphate, scale up, Signal Transduction, stereochemistry, Stereoisomerism, Swern oxidation, synthesis, unclassified drug, X ray crystallography
AbstractCyclic 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. © 2013 American Chemical Society.

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