Synthesis of anL-Fucose-Derived Cyclic Nitrone and its Conversion toα-L-Fucosidase Inhibitors

Abstract

The L‐fuco‐nitrone 1 has been synthesized from allyl 4,6‐O‐benzylidene‐α‐D‐glucopyranoside (4) in 11 steps and an overall yield of 18%. The key step is the intramolecular alkylation of an intermediary 1,1‐bis(hydroxylamine) derived from the tosyloxy oximes (E/Z)‐2. The nitrone 1 has been transformed into the diamine 30, the indolizidines 39 and 40, the indolizidinones 34 and 35, and the imidazole 44, all inhibiting bovine epididymis α‐L‐fucosidase with IC50 values between 105 nM and 240 μM.

Syntheses and Biological Activities of Iminosugars as α-L-Fucosidase Inhibitors

“…K i = 0.60 nM (bovine kidney)[44a] K i = 0.26 nM (Thermotoga maritima) [44b,45] K i = 0.06 nM (Thermotoga maritima)* [44b,45] K i = 9.7 nM (Human fucosidase) [44b,45] *Time dependent K i = 6 nM (bovine epididymis) [75] K i = 11 nM (human neutrophils) [75] IC 50 = 70 nM (Thermotoga maritima) [45] IC 50 = 92 nM (Human fucosidase) [45] IC 50 = 267 nM (Thermotoga maritima) [45] IC 50 = 106 nM (Human fucosidase)[45] K i = 30 (bovine kidney)[79] K i = 19 (bovine epididymis)[79] K i = 47 (Arthrobacter oxidans F 1 )[79] K i = 11 (bovine kidney)[79] K i = 8 (bovine epididymis)[79] K i = 1.5 (Arthrobacter oxidans F 1 )[79] IC 50 = 0.11 (bovine epididymis)[80] …”

Reversal of Stereoselectivity in Cycloadditions of Five‐Membered Cyclic Nitrones Derived from Hexoses

“…Unfortunately, one‐pot TBAF‐mediated desilylation (TBAF = tetra‐ n ‐butylammonium fluoride) and spontaneous ring‐closure did not give nitrone 4 in satisfactory yield and purity. To solve this problem, oxime 9 was conveniently desilylated, then the THF was replaced by a methanol/water mixture, and the cyclization was completed by adding a large excess of hydroxylamine hydrochloride/sodium hydrogen carbonate, followed by heating . Finally, the salts were removed by extraction, and nitrone 4 was isolated by flash column chromatography (FCC) in 81 % yield over two steps.…”

N-Alkyl-1,5-dideoxy-1,5-imino-l-fucitols as fucosidase inhibitors: Synthesis, molecular modelling and activity against cancer cell lines

“…N-Methylated-DFJ showed weak anti-HIV activity and no cytotoxicity in a study where various glycosidase inhibitors were screened [37]. Conformationally constrained N-alkyl DFJ derivatives were inhibitors of bovine epididymis -L-fucosidase [38]. An analogue of castanospermine with the L-fuco configuration and its fucosidase activity was described by Paulsen and co-workers [39].…”