Functionalized Glycomers as Growth Inhibitors and Inducers of Apoptosis in Human Glioblastoma Cells

Abstract

The effects of functionalized aryl beta-D-glycopyranosides (glycomers) on the proliferation, survival, and apoptosis of human glioblastoma cells in culture were evaluated as a way to control tumor progression. The results showed that inhibition of growth and/or induction of apoptosis can be achieved by these molecules in human glioblastoma cells. Inhibition of DNA synthesis precedes induction of apoptosis and growth inhibition. The substituents at C-1, C-2, C-3,C-4, and C-6 on the pyranosidic scaffold are important to modulate the action and the efficacy of these molecules. Human fibroblasts and brain-derived endothelial cells were less sensitive to glycomers than tumor cells. Thus, functionalized aryl beta-D-glycopyranosides represent a new class of molecules potentially able to control the progression of brain tumors.

Glycosylation Pathways as Drug Targets for Cancer: Glycosidase Inhibitors

“…All of these mechanisms would result in a modified metabolism of a protein, which may be either detrimental or beneficial to the organism, depending on the context. Small oligosaccharide and glycosidase inhibitors and their analogues have demonstrated efficacy in inhibiting several experimental and human cancers, uncluding glioblastoma and melanoma growth [17,[43][44][45][46][47][48]. High levels of glycosidases [49], mostly active at the C-1 position of the sugar backbone, have been found in thyroid, gastric and colon carcinoma [2,3,11,17,50-61], which have been hypothesized to be linked to defective maturation in the Golgi network of lysosomal -glycosidase in colon cancer cells [52].…”

“…Mechanism of enzymatic hydrolysis of glycosides by retaining and inverting glycosidases (# : reaction intermediate). The enormous structural variability of oligosaccharides defined by the sequence of sugar units, the anomeric orconfiguration and the positions of inter-residue linkages may provide opportunities for the development of banks of molecules with different properties [15][16][17]44]. Advances in understanding the role of glycosidases in various diseases have resulted in the development of new molecules or new analogues of known molecules [43,[68][69][70][71][72][73][74][75].…”

Structure‐Based Organic Synthesis of Drug Prototypes: A Personal Odyssey

“…Inhibition of growth was observed with aryl b-d-glycopyranosides containing ether, ester, and sulfonamide groups. [119,120] Although the exact mechanism of antiproliferative activity is not clear, it was established that these "glycomers" were inducers of apoptosis in glioblastoma cells. Furthermore, it was encouraging to realize that these compounds were capable of penetrating the cells in the lines tested.…”

Effects, in an in-vivo model system, of 1,2,3,4-tetrahydroisoquinoline on glioma

“…Wide ranges of therapeutic agents and strategies have been and are currently being applied against glioblastomas. These include toxins directed at extracellular protein domains [8], gene-based therapy using viral delivery systems [9][10][11], natural products such as curcumin [12], inorganic compounds such as selenite [13], and any of a number of others [14][15][16][17][18]. Many of these efforts were frustrated by the infiltrating nature of glioblastomas and the isolation of the brain by the physical and biological nature of the blood-brain barrier.…”