Synthesis of novel pyrrolidine 3,4-diol derivatives as inhibitors of alpha-L-fucosidases.
The stereoselective synthesis of new 3,4-dihydroxypyrrolidine derivatives starting from D-mannose, D-ribose and L-fucose is presented. Two synthetic strategies employing organometallic addition to hemiacetalic sugars followed by selective nucleophilic displacement or conjugate addition of ammonia to conjugate aldonic esters as key steps, are used. The new compounds were assayed for their inhibitory activity towards 13 commercially available glycosidases. Compounds that share the absolute configuration at C(2,3,4,5) of L-fucopyranosides and incorporate aromatic moieties are potent and selective inhibitors of alpha-L-fucosidases in the nM range.
Moreno-Clavijo
Elena
E
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, P.O. Box 553, E-41071, Sevilla, Spain.
Carmona
Ana T
AT
Vera-Ayoso
Yolanda
Y
Moreno-Vargas
Antonio J
AJ
Bello
Claudia
C
Vogel
Pierre
P
Robina
Inmaculada
I
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005643:Fucose / Q000737:chemistry; D008358:Mannose / Q000737:chemistry; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012266:Ribose / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors*
C540241:3,4-dihydroxypyrrolidine; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D005643:Fucose; D012266:Ribose; D005644:alpha-L-Fucosidase; D008358:Mannose