Intracellular distribution of new tacrine analogues as a potential cause of their cytotoxicity against human neuroblastoma cells SH-SY5Y

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...

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Published in:Medicinal chemistry research 2018-10, Vol.27 (10), p.2353-2365
Main Authors: Lucia, Krajňáková, Jana, Pisarčiková, Ladislav, Drajna, Martina, Labudová, Ján, Imrich, Helena, Paulíková, Mária, Kožurková
Format: Article
Language:English
Subjects:
Acetic acid
Acetylcholinesterase
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cell Biology
Cytotoxicity
Deoxyribonucleic acid
Derivatives
DNA
DNA topoisomerase
Intracellular
Localization
Lysosomes
Mitochondria
Neuroblastoma
Neuroblastoma cells
Nuclei (cytology)
Original Research
Pharmacology/Toxicology
Tacrine
Toxicity
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Summary: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 (IC 50 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.
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-018-2241-6