Title
Intracellular distribution of new tacrine analogues as a potential cause of their cytotoxicity against human neuroblastoma cells SH-SY5Y
Author
Lucia Krajňáková, Jana Pisarčiková, Ladislav Drajna, Martina Labudová, Ján Imrich, Helena Paulíková, Mária Kožurková
Year
2018
Journal
Medicinal Chemistry Research
Abstract
Four new glyco-conjugated tacrine derivatives, 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1-(1,2,3,4-tetrahydroacridin-9-yl)thiosemicarbazide (1), 4-(2,3,4,6-tetra-O-acetyl-β-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-β-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-β-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 µM, 72 h). 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.
Instrument
J-810
Keywords
Circular dichroism, DNA structure, Ligand binding, Biochemistry, Medicinal