Glyco- and peptidomimetics from three-component Joullié-Ugi coupling show selective antiviral activity.
Chlorination-elimination chemistry coupled with three-component Joullié-Ugi reaction and facile deprotection allowed efficient access to an array of polyhydroxylated pyrrolidines through parallel synthesis that may be considered to be a library of imino (aza) sugars (glycomimetics) and/or dihydroxyprolyl peptides (peptidomimetics). The utility of generating such a library was illustrated by screening against 15 different targets that revealed potent and selective inhibition of the Gaucher's disease glycosyltransferase enzyme glucosylceramide synthase and of primary pathogen model for human hepatitis C virus (HCV) and bovine diarrhoeal virus (BVDV). An observed selectivity for this HCV model over hepatitis B virus and remarkably low toxicity suggest a novel mode of action.
Chapman
Timothy M
TM
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford UK, OX1 3TA.
Davies
Ieuan G
IG
Gu
Baohua
B
Block
Timothy M
TM
Scopes
David I C
DI
Hay
Philip A
PA
Courtney
Stephen M
SM
McNeill
Luke A
LA
Schofield
Christopher J
CJ
Davis
Benjamin G
BG
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology; D002241:Carbohydrates / Q000737:chemistry / Q000494:pharmacology; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004896:Erythritol / Q000737:chemistry / Q000494:pharmacology; D006020:Glycopeptides / Q000737:chemistry* / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors; D006515:Hepatitis B virus / Q000187:drug effects; D006909:Hydroxyproline / Q000031:analogs & derivatives / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology; D013402:Sugar Alcohols / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D001372:Aza Compounds; D002241:Carbohydrates; D004791:Enzyme Inhibitors; D006020:Glycopeptides; D011759:Pyrrolidines; D013402:Sugar Alcohols; C003460:threitol; D006026:Glycoside Hydrolases; D004896:Erythritol; D006909:Hydroxyproline