Synthesis and evaluation of glycosidase inhibitory activity of octahydro-2H-pyrido[1,2-a]pyrimidine and octahydro-imidazo[1,2-a]pyridine bicyclic diazasugars.
An efficient chiron approach for the synthesis of bicyclic diazasugars 4a and 4b having both -CH(2)OH and -OH functionality at the same carbon atom (C-6) is reported. Thus, easily available alpha-D-xylo-pentodialdo-1,4-furanose 5, obtained from D-glucose, on aldol-crossed Cannizzaro reaction followed by hydrogenolysis afforded 7. The regio-selective beta- and alpha-sulfonylation of hydroxymethyl groups in 7 afforded 8a (beta-sulfonylation) and 11 (alpha-sulfonylation) in good yields. The cleavage of the 1,2-acetonide functionality, individually in 8a and 11, followed by reaction with ethylenediamine gave in situ formation of sugar aminals that undergo concomitant nucleophilic displacement of the sulfonyloxy group, by amino functionality, to give hitherto unknown bicyclic diazasugars 4a and 4b, respectively. The inhibitory potency of the earlier reported bicyclic diazasugars 3a,b and 4a,b was evaluated against alpha- and beta-glycosidases and they were found to be potent and specific against the beta-glycosidases with IC(50) and K(1) values in the micro molar range.
Dhavale
Dilip D
DD
Garware Research Centre, Department of Chemistry, University of Pune, Pune 411 007, India. ddd@chem.unipune.ernet.in
Matin
Mohammed M
MM
Sharma
Tarun
T
Sabharwal
Sushma G
SG
D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002241:Carbohydrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D010944:Plants / Q000201:enzymology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D001372:Aza Compounds; D002241:Carbohydrates; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D011725:Pyridines; D011743:Pyrimidines; D006026:Glycoside Hydrolases