Inhibitors of Fucosyltransferases

Cai, S, Stroud, M R, Hakomori, S, Toyokuni, T, Synthesis of carbocyclic analogs of guanosine 5 -(beta-L-fucopyranosyl diphosphate) (GDP-fucose) as potential inhibitors of fucosyltransferases, J. Org. Chem., 57, 6693-6696, 1992. 

R. Wischnat, R. Martin, C.-H. Wong, Synthesis of a New Class of N-Linked Lewis and LacNAc Analogues as Potential Inhibitors of Human Fucosyltransferases A General Method for the Incorporation of an Iminocyclitol as a Transition-State Mimetic of the Donor Sugar to the Acceptor , J. Org. Chem 1997, 63, 8361-8365. 

The iminoaltritol (74) as well as the iminogulitol (77) could also be shown to be moderate inhibitors of a recombinant human a-l,3-fucosyltransferase. 

A heptaprenylhydroquinone derivative (402) was isolated from an Indian sample of Ircinia fasciculata [341]. Ircinia spinulosa from the Adriatic contained three sulfated 2-prenylhydroquinones (403-405) that are toxic to brine shrimp [342]. An Ircinia sp. from New Caledonia contained a sulfated 2-prenylhydroquinone (406) and a sulfated furanoterpene (407) [343]. An Australian Sarcotragus sp. contained octaprenylhydroquinone sulfate (408) and nonaprenylhydroquinone sulfate (409) as inhibitors of al,3 fucosyltransferase VH [344]. 

Bryan MC, Lee LV, Wong CH. High-throughput identification of fucosyltransferase inhibitors using carbohydrate microarrays. Bioorg. Med. Chem. Lett. 2004 14 3185-3188. 

A potent inhibitor against human a(l,3)-fucosyltransferase VI was identified from a GDP-triazole library of 85 compounds, which was produced by the Cu(I)-catalyzed [2 + 3] cycloaddition reaction between azide and acetylene, followed by in situ screening without product isolation (O Scheme 13) [155]. Kinetic evaluation of the purified inhibitor (O Scheme 13) showed that it is a competitive inhibitor against GDP-fucose with Ki = 62 nM, which would make this compound the first nanomolar and most potent inhibitor of Fuc-Ts. 

Variations of the radical acceptor substitution pattern and use of acetobromogalactose 242 [106] or acetobromomannose 243 [107,108] as a radical precursor has resulted in the s)uithesis of various C-dimers including the C-linked analog of Man-o (l— 3)-GalNAc, which proved to be an inhibitor of several glycosidases, as well as human a-kS-fucosyltransferase VI [108] (O Scheme 49). 

Lee LV, MitcheU ML, Huang S-J, Eokin W, Sharpless KB, Wong C-H (2003) A potent and highly selective inhibitor of human a-1, 3-fucosyltransferase via click chemistry. J Am Chem Soc 125 9588-9589... 

Fleet and co-worker described the synthesis of L-C-fucoside analogue 68, locked in a 4 chair conformation, as potent inhibitor of fucosidases and weak inhibitor of a fucosyltransferase (Fig. 20). This a-L-fucose... 

In situ click chemistry was used to assemble inhibitors for acetylcholinesterase derived from tacrine and phenylphenanthridinium azides. The in situ generated inhibitors were extremely potent acetylcholinesterase inhibitors and care should be observed in handling these neurotoxic compounds. A potent inhibitor of human o -l,3-fucosyltransferase was similarly identified from a 1,2,3-triazole library of 85 compounds prepared by the [3-1-2] cycloaddition reaction of azides with terminal alkynes . Also, protein tyrosine phosphatase inhibitors are synthesized in a similar manner. ... 

From Unsaturated Sizars. - A trisubstrate analogue 30 has been synthesized (Scheme 7) as a potential inhibitor of the a-(l- 3)-fucosyltransferase that transfers fucose from GDP-fucose onto 0-3 of a 2-acetamido-2-deoxy-P-D-glucose residue. The glycosyl donor 29 was synthesized from the L-fuconolactone derivative 28 by methylenation and anti-Markovnikov azido-phenylselenation,... 

Scheme 8. Postulated transition-state structure and inhibitors of al,2-fucosyltransferase II.

Wakimoto, T, Maruyama, A, Matsunaga, S., Fusetani, N., Shinoda, K., and Murphy, P.T. (1999) Octa- and nonaprenylhydroquinone sulfates, inhibitors of a-l,3-fucosyltransferase Vll, from an Australian marine sponge Sarcotrugus sp. Biorg. Med. Chem. Lett., 9, 727-730. 

Taking advantage of the versatility ofthe Cu(I)-catalyzed 1,3-cycloaddition, Lee et al. developed an approach to synthesize and screen fucosyltransferase (Fuc-T) inhibitors in situ. Among the 85 compounds prepared, (34) was found to be a selective inhibitor of a-l,3-Fuc-T VI (IC50 =0.15pM) (Figure 10.7) [46]. 

Fucosyltransferases (glycosyltransferases) promote the transfer of fucose from GDP-fucose onto a saccharidic acceptor. This transfer occurs with inversion of the configuration of the anomeric carbon. The inhibition has been studied with fluorinated substrates. GDP-2-fluoro-2-deoxyfucoses (GDP-2F-fucose) and GDP-6-fluoro-6-deoxyfucoses (GDP-6F-fucose) are competitive inhibitors. The values are close to or less than that of (Figure 1.29)P The very close values of GDP-2F-fucose... 

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