Mannosidases inhibitor

Colgate, S. M., Dorling, P. R. and Huxtable, C. R. 1979. A spectroscopic investigation of swainsonine an a-mannosidase inhibitor isolated from Swainsona canescens. Austral. J. Chem. 32 2257-2264. 

Base-catalyzed nitromethane cyclization of the dialdehyde generated by periodate oxidation of 1,2-O-cyclohexylidene-myo-inositol affords the nitrodiol with 1,4/2,3,5-configuration. This is converted into the a-mannosidase inhibitor, mannostatin A (Eq. 3.60).98... 

U. Fuhrmann, E. Bause, G. Legler, and H. Ploegh, Novel mannosidase inhibitor blocking conversion of high mannose to complex oligosaccharides, Nature, 307 (1984) 755-758. 

M. Shibano, S. Kitagawa, and G. Kusano, Studies on the constituents of Broussonetia species. I. Two new pyrrolidine alkaloids, broussonetines C and D, as (l-galactosidasc and P-mannosidase inhibitors from Broussonetia kazinoki SIEB., Chem. Pharm. Bull., 45 (1997) 505-508. 

G. W. J. Fleet, P. W. Smith, S. V. Evans, and L. E. Fellows, Design synthesis and preliminary evaluation of a potent a-mannosidase inhibitor l,4-Dideoxy-l,4-imino-D-mannitol, J. Chem. Soc., Chem. Commun. (1984) 1240-1241. 

G. Limberg, I. Lundt, and J. Zavilla, Deoxyiminoalditols from aldonic acids. VI. Preparation of the four stereoisomeric 4-amino-3-hydroxypyrrolidines from bromodeoxytetronic acids. Discovery of a new a-mannosidase inhibitor, Synthesis (1999) 178-183. 

A. E. Hakansson, J. van Ameijde, L. Guglielmini, G. Home, R. J. Nash, E. L. Evinson, A. Kato, and G. W. J. Fleet, Looking glass inhibitors Synthesis of a potent naringinase inhibitor l-DIM (l,4-dideoxy-l,4-imino-L-mannitol), the enantiomer of DIM (l,4-dideoxy-l,4-imino-D-mannitol) a potent a-D-mannosidase inhibitor, Tetrahedron Asymmetry, 18 (2007) 282-289. 

Since the isolation of the chitinase inhibitor allosamidin from Streptomyces [90], the aminohydroxy-substituted cyclopentanes have been recognized as powerful and specific inhibitors of glycosidases [91]. The synthesis of (+) [92], as well as of racemic [93] mannostatin, which is a strong mannosidase inhibitor, should be mentioned here (Fig. 1). 

Due to the abundance and biological importance of the above mentioned enzymes, the areas of o-glucosidase as well as o-mannosidase inhibitors such as... 

To demonstrate the problems associated with ex-chiral-pool syntheses, some typical examples are given in this section. Three start with n-glucose, which is by far the most popular substrate in ex-chiral-pool synthesis, and illustrate the key transformations, in the first example, D-glu-cose is transformed into the mannosidase inhibitor iV-acetyl-4-deoxymannosamine by 4-deoxygenation and a SN2 displacement reaction of nitrogen introducing an amino function in place of a 2-hydroxy function 5. 

An amidrazone (58) derived from 5-amino-5-deoxy-L-fuconolactam was found to inhibit a recombinant human a-L-fucosidase with a Krvalue 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 mannosidase 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]. 

Tri-and tetra-hydroxyazepanes were shown to be potent glycosidase inhibitors <07JOC4258> while isofagomine tetrahydroxyazepane hybrids were synthesised as 0-glucosidase or mannosidase inhibitors <07CC183>. 

Alpha-1-antitrypsin mutations are associated with early-onset emphysema and liver disease that results in early death (50). The Z-variant of the disease is the most common and is present in over 95% of cases. This variant has been shown to be rescued in vitro by treatment with proteasome inhibitors (50). Several chemical and pharmacological chaperones have also been shown to correct the secretion of the mutant protein, which include the glucosidase inhibitor castanospermine, as well as the mannosidase inhibitors kifunensine (Fig. 2b)... 

Marcus NY, Perknutter DH. Glucosidase and mannosidase inhibitors mediate increased secretion of mutant alphal antitrypsin Z. J. Biol. Chem. 2000 275 1987-1992. 

For example, the 3-0-(5-thio-a-D-glucopyranosyl) derivative of 1-deoxymannojirimycin (60), a powerful D-mannosidase inhibitor, was synthesized as a potential inhibitor of endo-a-D-mannosidase of glycoprotein trimming [150]. 

Chemical syntheses have allowed investigations of structure-activity relationships, e.g., for mannosidase inhibitors [129,130], Some potent new inhibitors have been produced such as l,4-dideoxy-l,4-imino-D-mannitol (DIM) (41), an azafuranose analogue of mannose [131] which is a good mannosidase inhibitor but unlike 1-deoxymannojirimycin it does not inhibit Golgi a-mannosidase I. 1-Deoxymannojirimycin is a more potent inhibitor of a-L-fiicosidase than of a-D-mannosidase [132], 1-Deoxyfuconojirimycin (l,5-dideoxy-l,5-imino-L-fucitol) (DFJ) (42) is a synthetic potent and specific inhibitor of human liver a-L fucosidase. 

Irradiation of pyridinium perchlorate in dilute perchloric acid (Xirr = 254 nm) is reported to give an amino diol which can be acetylated to the corresponding amido-diacetate (186 R = Ac), and which itself can be converted into the a-mannosidase inhibitor (+)-mannostatin A (187). The photochemical rearrangement of 1-acetyl-l,2-dihydroquinoline-2-carbonitriles to 3,1-benzoxazines and cycloprop[b]indoles has been described, and photo-... 

Esters of swainsonine appear to offer therapeutic advantages in terms of specificity for Golgi a-mannosidase II, improved pharmacokinetics, and diminished side effects (143). Although 2- and 8-acyloxy esters of swainsonine were two to three orders of magnitude less active as a-mannosidase inhibitors in vitro than the parent alkaloid, the 2-butanoyl, 2-octanoyl, and 2-p-nitrobenzoyl esters, which are soluble enough to enter viable tumor cells, were as effective as swainsonine in vivo, apparently because they are hydrolyzed to swainsonine with intracellular esterases. These compounds may thus be advantageous as prodrugs. 

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