Intracellular distribution of new tacrine analogues as a potential cause of their cytotoxicity against human neuroblastoma cells SH-SY5Y
Abstrakt
Four new glyco-conjugated tacrine derivatives, 4-(2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)-1-(1,2,3,4-tetrahydroacridin-9-yl)thiosemicarbazide (1), 4-(2,3,4,6-tetra-O-acetyl--D-mannopyranosyl)-1-(1,2,3,4-tetrahydroacridin-9-yl)thiosemicarbazide (2), 2-(1,2,3,4-tetrahydroacridin-9-yl)hydrazono-3-(2,3,4,6-tetra-O-acetyl--D-galactopyranosyl)-1,3-thiazolidin-4-one (3) and [2-(1,2,3,4-tetrahydro-acridin-9-yl)hydrazono-3-(2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)-4-oxothiazolidin-5-yliden]acetate (4) were synthesized and their characteristics were investigated. All of the novel derivatives were found to inhibit acetylcholinesterase obtained from Electrophorus electricus at a magnitude of one order less than that of the control tacrine.
Derivatives 1-3 were found to be nontoxic towards human neuroblastoma SH-SY5Y cells, while compound 4 was markedly cytotoxic against these cells (IC50 value 2 mu M, 72h). These differences in cytotoxicity were examined further by investigating the uptake and intracellular localization of the tacrine derivatives.
Non-cytotoxic derivatives 1-3 were found to localize outside of the nuclei, showing a marked preference for the lysosomes and the mitochondria; in contrast, the cytotoxic derivative 4 was localized in the nuclei of the neuroblastoma cells. Interaction studies revealed that derivative 4 displays a high affinity towards DNA, and also provided evidence of the compound's ability to inhibit Topo I.