Design and Synthesis of Glycoside Inhibitors of Glioma and Melanoma Growth

Abstract

An N-acetylglucosaminide derivative with a pentaerythritol substituent at position C-6 was previously synthesized and shown to inhibit neural tumor growth. Now, we report the preparation of a series of new synthetic compounds introducing systematic changes in the nature, polarity, and size of the sugar substituents. The antimitotic activity of the new compounds was tested on cultured rat (C6) and human (U-373) glioma lines and on a human melanoma line (A-375). The antimitotic and antitumoral activity of the new compounds on glioma cell lines increased up to 2 orders of magnitude with respect to the parent compound or was abolished, permitting a detailed structure-function analysis of the new antitumorals. One of the glycosides inhibited melanoma division with an ID50 below the micromolar range.

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by 1H MAS NMR

“…22 Interestingly, compound 1 is a glycoside of oleyl alcohol, and the presence of the oleyl group was the main structural difference with respect to the parent glycosides that resulted less inhibitory of glioma cell division than 1. 7 The treatment of C6 cells with oleic acid (100 µM) for 24 h afforded a 1 H NMR spectrum similar to that obtained with 1 (10 µM) (Figure 1c), in which the major metabolic change was also the intensity of the signal at 0.67 ppm. In this case, a 3-fold decrease in the peak intensity from CoA metabolites was observed.…”

“…2 On the basis of structural elements of the natural inhibitor, we synthesized series of oligo-and monosaccharides, which were tested as inhibitors of brain tumor cell division. [3][4][5][6][7] Recently we have obtained a family of N-acyl-glucosamine derivatives, some of which showed antimitotic activity against rat C6 glioma cells with low IC 50 values. 7 The results obtained indicated that the activity was increased by a long hydrocarbon chain at position C-1 of the glucosamine backbone, the most inhibitory compound being the oleyl glycoside 1 (Chart 1).…”

Novel sulfoglycolipid IG20 causes neuroprotection by activating the phase II antioxidant response in rat hippocampal slices

“…Sulfoglycolipid IG20 seems to belong to this last group of compounds that exert neuroprotection through a mechanism that involves a given cellular signalling pathway. In line with this proposal are the various families of glycolipids and sulfoglycolipids synthesised at our laboratory that by acting on intracellular signalling pathways exhibit antimitotic activity in melanoma and glioma cells (Doncel-Perez et al, 2013;Garcia-Alvarez et al, 2007). In this line is IG20 that belongs to a new family of sulfoglycolipids that emerged in the context of the synthesis of new antineoplasic agents with potential therapeutic application in glioma and melanoma, and that promoted neuritic growth and myelination (Garcia-Alvarez et al, 2015).…”

“…This last property mainly focused the treatment of cerebral gliomas (Doncel-Perez et al, 2013;FernandezMayoralas et al, 2003;Garcia-Alvarez et al, 2007). The synthetic strategy was inspired in the fact that in mammalian brain there are natural inhibitors of astroblasts and astrocytes division (Nieto-Sampedro, 1988;Nieto-Sampedro and Broderick, 1989); one such inhibitor is neurostatin, first found in the rat brain (Valle-Argos et al, 2010).…”

“…Thus, the simple compound IG20 was synthesised and although with lesser potency, it shared with neurostatin its ability to inhibit gliomas growth (Garcia-Alvarez et al, 2007). Recently, IG20 was shown to inhibit astrocyte and microglia proliferation, the main cellular components of the glial scar, and promote axonal outgrowth and myelin production in vitro (Garcia-Alvarez et al, 2015).…”