1-Thio- -D-galactofuranosides: synthesis and evaluation as  -D-galactofuranosidase inhibitors

Abstract

Beta-D-galactofuranosidase is a good chemotherapeutic target for the design of inhibitors, since beta-D-galactofuranose is a constituent of important parasite glycoconjugates but is not present in the host mammals. With this aim, we have synthesized for the first time alkyl, benzyl and aryl 1-thio-beta-D-galactofuranosides by condensation of penta-O-benzoyl-alpha,beta-D-galactofuranose with the corresponding thiols, in the presence of SnCl4as catalyst. The complete chemical and spectroscopical characterization of these compounds showed that the reaction was stereoselective. Debenzoylation with sodium methoxide afforded the beta-S-galactofuranosides in high yield. The thioglycosides were tested as inhibitors of the beta-D-galactofuranosidase of Penicillium fellutanum, using for the first time 4-nitrophenyl-beta-D-galactofuranoside as chromogenic substrate. The 4-aminophenyl-1-thio-beta-D-galactofuranoside, obtained by catalytic hydrogenation of the nitrophenyl derivative, was the best inhibitor being then an adequate ligand for the preparation of an affinity phase aimed at the isolation of beta-d-galactofuranosidases from different sources. Also the inhibitory activity of d-galactono-1, 4-lactone was shown.

Synthesis of heteroaryl 1-thio-ß-D-galactofuranosides and evaluation of their inhibitory activity towards a ß-D-galactofuranosidase

“…4-Nitrophenyl β-D-galactofuranoside (10) was used as substrate, and lactone 9 was tested as a reference inhibitor (IC50 0.10 mM). 25 The enzymatic reaction was performed in the presence of thioglycosides 14b-16b, 18b and 19b at concentrations ranging from 0.15 to 1.25mM. We found that compounds 14b-16b, 18b are weak inhibitors (Figure 2), whereas 19b is a stronger inhibitor (IC50 135 µM).…”

Two Straightforward Strategies for the Synthesis of Thiodisaccharides with a Furanose Unit as the Nonreducing End

“…Thus, a solution of 1a and thiourea in acetonitrile was heated under reflux in the presence of BF 3 ·OEt 2 to afford α-S-glycosyl isothiourea 2 (Scheme 1). In the NMR spectra of 2, the C-1 signal showed a strong upfield shift (relative to that of 1a) as observed for thioglycosylation of per-O-acylated furanoses [11,13] and the J 1,2 value (Ͻ1 Hz) indicated the α configuration for the anomeric center (1,2-trans thioglycoside). [19,20] As benzoylation of arabinose also provides β anomer 1b, the reaction of this compound with thiourea was conducted under the conditions employed for isomer 1a; Sglycosyl isothiourea 2 was obtained in good yield.…”

“…As 4-H is coupled with the adjacent methylene protons, the small coupling constant values (J 3ax,4 = 4.7 Hz, J 3eq,4 = 1.8 Hz) indicate that 4-H is equatorially oriented. Furthermore, the small value for the coupling between 1Ј-H and 2Ј-H (J 1Ј,2Ј Ͻ 1 Hz) is indicative of an 1Ј,2Ј-trans stereochemistry [11,13] (α anomeric configuration) for the furanose. Michael addition to sugar enone 3 was studied for other per-O-acylated furanoses.…”

“…[10] Recently, thioimidoyl α--arabinofuranosides have been described as the first potent inhibitors of an arabinofuranosidase. [11] In view of the previous considerations and in connection with our studies on the synthesis and inhibitory activity of S-linked saccharides, [12][13][14] we explored the construction of thiodisaccharides containing a pentofuranose unit as potential inhibitors of pentofuranosidases. We report here two successful approaches for the synthesis of such thiodisaccharides starting from readily available per-O-acylated pentofuranoses.…”

Recent knowledge and innovations related to hexofuranosides: structure, synthesis and applications

“…215,216 The thiogalactofuranosides (Fig. 23) were easily obtained in good yields (generally higher than 85%) by S-glycosylation of penta-O-benzoyl-galactofuranose in the presence of 3 Following that example, we have recently synthesized a series of thioimidoyl furanosides as inhibitors of the a-L L-arabinofuranosidase AbfD3.…”