Thio-glycomimetics with enhanced lipophilicity and their biological activity

Abstract

The thio-linked glycomimetics were prepared via a base-catalyzed, highly stereo-selective Michael condensation of levoglucosenone with various sugar, heterocyclic and adamantane thiols in order to generate a library of analogs with comparative level of lipophilicity for further biological screening as antibacterial and anticancer agents. The comparative analysis of earlier synthesized library of previously synthesized glycomimetics with the new analogs exhibiting more lipophilic character is also presented. 1 H NMR, 13 C NMR, and single-crystal x-ray diffraction of the unexpected addition and cyclization product unequivocally confirm the structural assignments. Mechanistic insights related to the synthesis of new products are also proposed and discussed.

Synthesis of thiodisaccharides related to 4-thiolactose. Specific structural modifications increase the inhibitory activity against E. coli β-galactosidase

“…3 Hz, H-6′b), 3.88 (td, J 4′,5′ = 1.2, J 5′,6á = J 5′,6′b ≈ 6. 7 Hz, H-5′), 3.74 (ddd, 1H, J 3a,4 = 4.9, J 3b,4 ≈ J 4,5 ≈ 2. 4 Hz, H-4), 3.19 (dd, 1H, J 3a,3b = 15.5, J 3a,4 = 4.9 Hz, H-3a), 2.89 (dd, 1H, J 1,3eq = 0.9, J 3a,3b = 15.5, J 3b,4 = 2.7 Hz, H-3b), 2.15, 2.09, 2.07, 2.04, 1.98 (5s, 15H, CH 3 CO); 13 General procedure for the conjugate addition of 2 to enones derived from hexoses (3 or 10) at a high temperature Sugar enone 3 (364 mg, 1.32 mmol) or 10 (425 mg, 1.32 mmol) and 1-thioaldose 2 (480 mg, 1.32 mmol) were dissolved in dry CH 3 CN (4.5 mL).…”

“…4 Hz, H-6′b), 3.93 (td, 1H, J 4′,5′ = 1.0, J 5′,6′a = J 5′,6′b = 6. 7 Hz, H-5′), 3.70 (br ddd, 1H, J 1,2 < 1.0, J 2,3a ≈ 3.9, J 2,3b ≈ 3.0, J 2,OH = 10.1 Hz, H-2), 3.55 (d, 1H, J 2,OH = 10.1 Hz, OH), 3.36 (br td, 1H, J 3a,4 ≈ 3.9, J 3b,4 ≈ J 4,5 = 3.0 Hz, H-4), 2.33 (td, 1H, J 2,3a ≈ J 3a,4 ≈ 3.9, J 3a,3b = 15.0 Hz, H-3a) 2.28 (td, 1H, J 2,3b ≈ J 3b,4 ≈ 3.0, J 3a,3b = 15.0 Hz, H-3b), 2.17, 2.09, 2.07, 2.05, 2.00 (5s, 15H, CH 3 CO); 13 The second product (R f 0.41) that was eluted from the column was 6 (45 mg, 47%); [α] 20 D +32.7 (c 0.8, CHCl 3 ); 1 H NMR (CDCl 3 , 500 MHz) δ 7.39-7.31 (m, 5H, Ph), 5.42 (dd, 1H, J 3′,4′ = 3.4, J 4′,5′ = 1.2 Hz, H-4′), 5.21 (t, 1H, J 1′,2′ = J 2′,3′ = 10.0 Hz, H-2′), 5.03 (dd, 1H, J 2′,3′ = 9.9, J 3′,4′ = 3.3 Hz, H-3′), 4.93 (d, 1H, J 1,2 = 3.7 Hz, H-1), 4.77, 4.52 (2 d, 2H, J = 11.5 Hz, OCH 2 Ar), 4.55 (d, 1H, J 1′,2′ = 10.0 Hz, H-1′), 4.28 (ddd, 1H, J 4,5 = 2.5, J 5,6a = 4.6, J 5,6b = 6.9 Hz, H-5), 4.22-4.16 (m, 2H, H-6a,6b), 4.17 (dd, 1H, J 5′,6′a = 6.7, J 6′a,6′b = 11. 4 Hz, H-6′a), 4.07 (dd, 1H, J 5′,6′b = 6.5, J 6′ a,6′b = 11.…”

“…In the last few decades, many efforts have been focused on the design, synthesis and application of new glycomimetics as biologically active molecules. [4][5][6][7] Glycomimetics have been used for different purposes and an area of growth is their use as inhibitors of enzymes that are involved in key biological processes. [8][9][10][11][12][13][14] They are commonly recognized by enzymes, but often show resistance to hydrolysis and metabolic degradation and in many cases act as enzyme inhibitors.…”

“…Among the glycosidase inhibitors, thiooligosaccharides have been shown to be effective inhibitors of E. coli β-galactosidase. 7,21 Thiooligosaccharides are sugar mimetics that have one (or more) oxygen atom of the interglycosidic bond replaced by a sulfur atom. They constitute convenient tools for the comprehension and interference of many biological processes and are particularly useful for studying carbohydrate-protein interactions and the hydrolysis step triggered by glycoside hydrolases.…”

“…In the last few decades, many efforts have been focused on the design, synthesis and application of new glycomimetics as biologically active molecules. 4–7 Glycomimetics have been used for different purposes and an area of growth is their use as inhibitors of enzymes that are involved in key biological processes. 8–14…”