A-L-Fucosidases

The guanidino analogue 90 of the 7-membered cyclic urea system was prepared, enantiomerically pure, from D-mannitol. The derivative 90 selectively inhibits bovine kidney a-L-fucosidase at 2.8pM <00BMC307>. 

Instead of a triflate, the electrophile on the glycosyl acceptor can be an a,(3-unsaturated carbonyl group. This is the case reported in Fig. 25, in which a stereoselective Michael addition of the 1-thiosugar 56 to the a,(3-conjugated system of levoglucosenone 57, generated after deprotection a couple of L-fucopyranosyl-4-thiodisaccharides 61 and 62 presenting inhibitory activity on a-L-fucosidase.54... 

A. Lammerts van Bueren, A. Ardevol, J. Fayers-Kerr, B. Luo, Y. Zhang, M. Sollogoub, Y. Bleriot, C. Rovira, and G. J. Davies, Analysis of the reaction coordinate of a-L-fucosidases A combined structural and quantum mechanical approach,./. Am. Chem. Soc., 132 (2010) 1804-1806. 

M. Nagae, A. Tsuchiya, T. Katayama, K. Yamamoto, S. Wakatsuki, and R. Kato, Structural basis of the catalytic reaction mechanism of novel 1,2-a-L-fucosidase from Bifidobacterium bifidum, J. Biol. Chem., 282 (2007) 18497-18509. 

The inhibitory activity of compound (42) (Scheme 13) was examined during the hydrolysis of p-nitrophenyl a-L-fucopyranoside by a-L-fucosidases. As reported above, this compound showed mixed inhibition [32]. 

In the series of a-L-fucopyranosyl-thio-glycosides, the most powerful inhibitor of a-L-fucosidases was the a(l ->3) linked isomer obtained by deprotection of the disaccharide (65 b). It has been shown to be a competitive inhibitor (Kj= 0.65 mmol/1) [32]. 

Less active derivatives might therefore be desirable in some cases. In this context, Paulsen and co-workers synthesized a range of chain-extended as well as bicyclic analogues of 1-deoxyfuconojirimydn, amongst others the 6-C-ethyl (54) and 6-C-methyl derivatives as well as l-deoxy-6,7,8-a-tri-epi-castanosper-mine (55). All of these derivatives exhibited considerable inhibitory activities towards a-L-fucosidase and were slightly to appreciably less active than the parent compound [107]. In an attempt to design a simple synthesis of 1-deoxy-... 

An amidrazone (58) derived from 5-amino-5-deoxy-L-fuconolactam was found to inhibit a recombinant human a-L-fucosidase with a K -value of 820 nmol/1 [ 111 ]. A simple synthesis of 1,5-dideoxy-1,5-imino-D-arabinitol (59), previously prepared by Ganem et al. [49] as a potential maimosidase inhibitor, was applied to the affinity purification of a-L-fucosidase from bovine kidney by an improved method and the characterization of the enzyme thus obtained [112]. The relatively low affinity of this compound to the enzyme (Kj 2.2 pmol/1 at pH 7) compared to 1-deoxyfuconoJirimycin (51) turned out to be advantageous in terms of enzyme recovery and yield. Structurally related, suitably protected 5-amino-5-deoxy-D-arabinopyranose (60), was coupled with a N-acetyl-6-deoxy-6-thio-D-glucosaminide (61) to give a stable thioglycoside (62) [113]. 

A L-/wco-related analogue (71) of isofagomine [61], which was recently prepared from D-ribose by Ichikawa et al. following previously established chemistry [63,121], was found to be an a-L-fucosidase inhibitor with Kj 8 pmol/1. No inhibition was found with tetrazole derivatives such as (72) [ 122] obtained from L-gulonolactone. 

Fucosidase inhibiting l,4,5-trideoxy-l,4-imino-L-lyxitol (78) was prepared [124] from D-ribose via protected 5-amino-5-deoxy-L-lyxose (79) by a chemical route. This compound, as well as the 1-aminomethyl homologue (80), obtained by Kiliani-Fischer chain extension of (79), inhibited a-L-fucosidase with K around 2 pmol/1. l,4-Dideoxy-l,4-imino-D-iditol (81) [71] was found to be a moderate inhibitor of the enzyme. 

Certain studies have sought to correlate the immunological identities of a-L-fucosidases from various mammalian sources, with a view to their utilization in replacement therapy in cases of lysosomal disorders involving this enzyme.266... 

Inhibitors of some of these enzymes have been reported. Usually, L-fucose inhibits at higher concentrations as do certain aldonolac-tones.258 L-Fucono-1,4-lactone was found to be a specific inhibitor for porcine-kidney a-L-fucosidase,287 although it had been reported257 that the crude enzymes from rat epididymis and ox liver were not inhibited by this lactone. 

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