100937-52-8Relevant articles and documents
Iminosugars as potential inhibitors of glycogenolysis: Structural insights into the molecular basis of glycogen phosphorylase inhibition
Oikonomakos, Nikos G.,Tiraidis, Costas,Leonidas, Demetres D.,Zographos, Spyros E.,Kristiansen, Marit,Jessen, Claus U.,N?rskov-Lauritsen, Leif,Agius, Loranne
, p. 5687 - 5701 (2006)
Iminosugars DAB (5), isofagomine (9), and several N-substituted derivatives have been identified as potent inhibitors of liver glycogen phosphorylase a (IC50 = 0.4-1.2 μM) and of basal and glucagon-stimulated glycogenolysis (IC50 = 1-3 μM). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 in complex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalytic site in the presence of the substrate phosphate and induce conformational changes that characterize the R-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with the carbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Our findings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformational change to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor the T state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase.
Synthesis of hydroxylated pyrrolidines by allenic cyclisation
Ng, Pearly Shuyi,Bates, Roderick W.
, p. 6356 - 6362 (2016)
The diastereoselective gold(I) catalysed cyclisation of highly substituted aminoallene derivatives allows the synthesis of both epi-DAB-1 and di-epi-lentiginosine. While the sense of stereoselectivity observed is in line with earlier observations on analo
Anin vitro-in vivosequential cascade for the synthesis of iminosugars from aldoses
Kuska, Justyna,O'Reilly, Elaine,Ryan, James,Taday, Freya,Yeow, Kathryn
, p. 4327 - 4331 (2021/07/12)
Here, we report a chemoenzymatic approach for the preparation of a small panel of biologically important iminosugars from readily available aldoses. Our approach involves anin vitrotransaminase-mediated amination of aldoses in combination with anin vivose
Structural essentials for β-: N -acetylhexosaminidase inhibition by amides of prolines, pipecolic and azetidine carboxylic acids
Glawar,Martínez,Ayers,Hollas,Ngo,Nakagawa,Kato,Butters,Fleet,Jenkinson
, p. 10371 - 10385 (2016/11/18)
This paper explores the computer modelling aided design and synthesis of β-N-acetylhexosaminidase inhibitors along with their applicability to human disease treatment through biological evaluation in both an enzymatic and cellular setting. We investigated the importance of individual stereocenters, variations in structure-activity relationships along with factors influencing cell penetration. To achieve these goals we modified nitrogen heterocycles in terms of ring size, side chains present and ring nitrogen derivatization. By reducing the inhibitor interactions with the active site down to the essentials we were able to determine that besides the established 2S,3R trans-relationship, the presence and stereochemistry of the CH2OH side chain is of crucial importance for activity. In terms of cellular penetration, N-butyl side chains favour cellar uptake, while hydroxy- and carboxy-group bearing sidechains on the ring nitrogen retarded cellular penetration. Furthermore we show an early proof of principle study that β-N-acetylhexosaminidase inhibitors can be applicable to use in a potential anti-invasive anti-cancer strategy.
