Convergent and stereoselective synthesis of iminosugar-containing Galf and UDP-Galf mimicks: evaluation as inhibitors of UDP-Gal mutase.
The synthesis of a UDP-Galf analog incorporating a 1,4-dideoxy-1,4-imino-d-galactitol skeleton alpha-linked to UMP by a 3C-tether and of a series of related pyrrolidine galactofuranose mimicks is reported. These compounds were obtained by way of the highly stereoselective reaction of silylated nucleophiles with a N-Cbz glucofuranosylamine which afforded the corresponding open-chain product with a 1,2-syn stereochemistry, as predicted from pionneering studies from Kobayashi. Cyclization of these intermediates afforded alpha-C-glycosides of imino-galactofuranose carrying various functional groups in the aglycone. Further elaboration of the alpha-C-allyl substituted derivative by cross-metathesis with a uridin-5'-yl vinylphosphonate provided, after deprotection, the desired original UDP-Galf mimicks. Cleavage of the benzyl ether protecting groups in the iminosugar component using BCl3 proved critical to the success of the synthetic plan. Several of the new 1,4-dideoxy-1,4-imino-d-galactitol derivatives were evaluated as inhibitors of UGM (UDP-galactopyranose mutase) from Escherichia coli; however, none of them exhibited less than mM activities toward this enzyme which catalyzes a crucial step of the biosynthesis of galactofuranose-containing bacterial cell-surface glycans.
Liautard
Virginie
V
Institut de Chimie Organique et Analytique, Université d'Orléans, CNRS-UMR 6005, BP 6759, 45067 Orléans, France.
Desvergnes
Valérie
V
Itoh
Kenji
K
Liu
Hung-wen
HW
Martin
Olivier R
OR
D000588:Amines / Q000737:chemistry; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D005690:Galactose / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007097:Imines / Q000737:chemistry*; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000737:chemistry; D013237:Stereoisomerism
D000588:Amines; D004791:Enzyme Inhibitors; D007097:Imines; D011760:Pyrrolidinones; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase; D005690:Galactose