Synthesis and characterization of neurostatin-related compounds with high inhibitory activity of glioma growth.
O-acetyl-ganglioside neurostatin, (Galbeta1-->3GalNAcbeta1-->4[9-O-Ac Neu5Acalpha2-->8Neu5Acalpha2-->3]Galbeta1-->4Glcbeta1-->1'-ceramide), is a natural GD1b-derived inhibitor of astroblast and astrocytoma division, whose structure and purification method limits its availability and stability. Therefore, we set-up the reaction to obtain O-acetylated and O-butyrylated neurostatin analogs by chemical synthesis, in order to improve its availability and stability. The compounds antitumoral activity was evaluated on U373MG and C6 glioblastoma cells, observing that the O-acetylation-dependent increase in the inhibitory activity was enhanced by O-butyrylation, with no further improvement with the multi-substitution, pointing to the initial conformational change and the stability change as responsible of its function. These results open the possibility for the application of the neurostatin-related compounds to in-vivo tumoral models.
Neural Plasticity Group, Functional and Systems Neurobiology Department, Cajal Institute (CSIC), Avda Doctor Arce, 37, 28002, Madrid, Spain.
Beatriz
B
Valle-Argos
Diego
D
Gómez-Nicola
Manuel
M
Nieto-Sampedro
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006028:Glycosphingolipids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D006028:Glycosphingolipids; C116059:neurostatin