RESUMO
Protecting group-free synthesis of 1,2:5,6-di-anhydro-D-mannitol, followed by ring opening with propargylamine and subsequent ring closure produced a separable mix of piperidine N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and azepane N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol. In O-acetylated form, these two building blocks were subjected to CuAAC click chemistry with a panel of three differently azide-substituted glucose building blocks, producing iminosugar pseudo-disaccharides in good yield. The overall panel of eight compounds, plus 1-deoxynojirimycin (DNJ) as a benchmark, was evaluated as prospective inhibitors of almond ß-glucosidase, yeast α-glucosidase and barley ß-amylase. The iminosugar pseudo-disaccharides showed no inhibitory activity against almond ß-glucosidase, while the parent N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol likewise proved to be inactive against yeast α-glucosidase. Inhibitory activity could be reinstated in the former series by appropriate substitution on nitrogen. The greater activity of the piperidine could be rationalized based on docking studies. Further, potent inhibition of ß-amylase was observed with compounds from both the piperidine and azepane series.
Assuntos
Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos com 1 Anel/síntese química , Imino Açúcares/síntese química , Piperidinas/síntese química , Triazóis/síntese química , alfa-Glucosidases/química , beta-Amilase/química , beta-Glucosidase/química , 1-Desoxinojirimicina/química , Azidas/química , Química Click/métodos , Dissacarídeos/química , Inibidores Enzimáticos/química , Glucose/química , Compostos Heterocíclicos com 1 Anel/química , Hordeum/química , Hordeum/enzimologia , Imino Açúcares/química , Manitol/química , Pargilina/análogos & derivados , Pargilina/química , Piperidinas/química , Propilaminas/química , Prunus dulcis/química , Prunus dulcis/enzimologia , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/enzimologia , Triazóis/química , beta-Amilase/antagonistas & inibidores , beta-Glucosidase/antagonistas & inibidoresRESUMO
Reaction of 2-(2-(2-azidoethoxy)ethoxy)ethyl 6-O-(prop-2-ynyl)-ß-d-galactopyranoside (7) under CuAAC conditions gives rise to mixed cyclic and linear triazole-linked oligomers, with individual compounds up to d.p. 5 isolable, along with mixed larger oligomers. The linear compounds resolve en bloc from the cyclic materials by RP HPLC, but are separable by gel permeation chromatography. The triazole-linked oligomers-pseudo-galactooligomers-were demonstrated to be acceptor substrates for the multi-copy cell surface trans-sialidase of the human parasite Trypanosoma cruzi. In addition, these multivalent TcTS ligands were able to block macrophage invasion by T. cruzi.
RESUMO
Trypanosoma cruzi trans-sialidase (TcTS) plays a key role in the recognition and invasion of host cells and in enabling the parasite to escape the human immune response. To explore this potential drug target, we have synthesized a small library of substrate analogues based on 1,4-disubstituted 1,2,3-triazole derivatives of galactose modified at either the C-1 or C-6 positions. This was achieved by coupling the appropriate azido-sugars with a panel of 23 structurally diverse terminal alkynes by using the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction, giving a library of 46 derivatives in good to excellent yield and with complete regioselectivity. The sugar triazoles showed weak inhibition towards TcTS-catalyzed hydrolysis of 2'-(4-methylumbelliferyl)-alpha-d-N-acetylneuraminic acid in vitro (<40% inhibition at 1mM concentration); many of the compounds assessed proved to be acceptor substrates for the enzyme. Despite this modest inhibitory activity, in vitro trypanocidal activity assays against the trypomastigote form of T. cruzi Y strain revealed several compounds active in the low 100s of muM range. Further assessment of these compounds against cultured mouse spleen cells suggests a specific mode of anti-parasite action rather than a generic cytotoxic effect.