Synthesis of new potentially biologically active sulfur- and selenium-containing carbohydrate derivatives

Abstract

Lectins, as carbohydrate-binding proteins, are capable of sticking cells (agglutination), are found in plants, humans, and pathogenic organisms and have a natural protective effect against various diseases and pathogens. The carbohydrate recognition abilities of lectins are targeted in the research and development of new drugs. Galectins have a broad specificity, regulating cell death intracellularly and extracellularly; they play a role in many diseases: cancer, autoimmune diseases, chronic inflammations. Gal-3- which is a chimera type galectin- expression is associated with various fibrosis, cancer cell growth, apoptosis, immunosuppression and metastasis. Galectin-3 is being used as a diagnostic marker for different cancers. Gal-3 has an affinity for β-galactosides, many studies reports various structured of Gal-3 inhibitors. The most widespread lung pathogen, the Gram-negative bacterium P. aeruginosa, produces LecA lectin. Several glycomimetics have been developed based on D-galactose for LecA, analyzed in vitro assays and showed excellent properties to block LecAmediated host cell binding and decrease bacterial invasion into human cells. During our research, we synthesized new, sulfur and selenium containing carbohydrate derivatives, as potential Gal-3 and LecA lectin inhibitors. Examination of the binding of selenium-containing derivatives is possible with 77Se NMR techniques. High-yielding synthetic route of TDG and SeDG we worked it out; a procedure for the synthesis of the novel 3,3′-di-O-(quinoline2-yl)methyl)-TDG and three other known, symmetric 3,3′-di-OTDG derivatives ((naphthalene-2yl)methyl, benzyl, (7-methoxy2H-1-benzopyran-2-on-4-yl)methyl) was optimized. Based on the biological effect of 3,3’-di-O-aralkyl-TDG derivatives, we prepared new quinoline-2-ylmethyl 32 and naphthalene-2-ylmethyl 26 SeDG derivatives started from monosaccharide derivatives. We have developed a new method for the removal of PMP groups in the starting compounds, using the Selectfluor® reagent, which method is suitable for the selective removal of the PMP group from 2 NAP and quinolin-2-ylmethyl groups. Divalent selenogalactoside derivatives containing a 1,2,3-triazole ring were synthesized by a Cu(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) reaction, as potencial divalent LecA inhibitors. The benzene 42, naphthalene 43, 1,1’-biphenyl 44 and pyridine 45 di(azidomethyl) derivatives were formed in good yield from the corresponding aromatic dibromides in DMF with sodium azide in reactions. Prop-2-yn-1-yl 2,3,4,6-tetra-O-acetyl-β-d-selenogalactopyranoside 33 was prepared from isoselenouronium salt 5. Reaction of di(azidomethyl) derivatives 38-41 with prop2-yn-1-yl 2,3,4,6-tetra-O-acetyl-β-d-selenogalactopyranoside afforded -seleno-β-d-galactopyransides 42-45. Homo- and heteroaromatic dimethyl diazides 42-45 ctowere synthesized from the corresponding bromides in dry DMF at room temperature in good yields. The removal of the acetyl protecting groups by the Zemplén method provided the bifunctional aralkyl 1,2,3-triazolo-seleno-β-d-galactopyranoside derivatives in good yields. New aralkyl 1-seleno-β-d-galacto- and glucopyranosides 55, 56, 55a, 56a were synthesized to expand the repertoire of monovalent derivatives, started from 2,3,4,6-tri-O-acetyl-β-d-glycopyranosyl isoselenouronium salts 5, 51 by reactions with 2-(bromomethyl) quinolin and 4-bromomethyl-7-methoxycoumarin under mild reaction conditions. Gluco-derivatives will be used as competitive ligands in binding studies. Gal-3 is known to be highly upregulated during infection with the African sleeping sickness parasite T. brucei. In parallel with the lectin binding studies, within the framework of foreign cooperation, the new selenoglycosides 52-53 and 52a-53a were tested in T. brucei (African sleeping sickness) parasitological studies by Professor Dr. Marcelo Comini of the Pasteur Institute in Montevideo. During the biological tests, it was established that the presence of the acetyl group is beneficial in terms of the bioactivity of the compounds. In order to further increase bioactivity, we also synthesised new fluorine-containing selenogalactoside derivatives. From 2-deoxy-2-fluoro-3,4,6-tri-O-acetylβ-d-galactopyranosyl-isoselenouronium bromide we prepared naphtalene-2-ylmethyl, quinolin-2-ylmethyl and 7-methoxycoumarin-4-ylmethyl derivatives. According to the results of parasitological tests with T. brucei, derivatives 52a (EC50 1.2 ± 0.1 µM) and 56 (EC50 4.1 ± 1.0 µM) were found to be active. Collaborative partners of Dr. Marcelo Comini in South Korea investigated SARS-CoV-2 antiviral activity, according to which derivatives 63 (EC50 21.3 µM) and 64 (EC50 29.5 µM) were active.