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Medicinal Chemistry Research

, Volume 27, Issue 10, pp 2353–2365 | Cite as

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

  • Krajňáková Lucia
  • Pisarčiková Jana
  • Drajna Ladislav
  • Labudová Martina
  • Imrich Ján
  • Paulíková Helena
  • Kožurková MáriaEmail author
Original Research
  • 116 Downloads

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 13 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 13 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.

Keywords

Glyco-tacrine conjugates Tacrine Acetylcholinesterase inhibitors DNA SH-SY5Y cells 

Notes

Acknowledgements

This work was supported by the Slovak Grant Agency VEGA, Grant nos. 1/0001/13 and 1/0790/14, KEGA 002UPJŠ-4/2015, UHHK 00179906 and Structural Funds EU (ITMS: 26240220071).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Krajňáková Lucia
    • 1
  • Pisarčiková Jana
    • 1
  • Drajna Ladislav
    • 2
  • Labudová Martina
    • 3
  • Imrich Ján
    • 2
  • Paulíková Helena
    • 1
  • Kožurková Mária
    • 2
    • 4
    Email author
  1. 1.Department of Biochemistry and MicrobiologyFaculty of Chemical and Food TechnologyBratislavaSlovakia
  2. 2.Department of Biochemistry, Institute of ChemistryP.J. Safarik UniversityKošiceSlovakia
  3. 3.Slovak Academy of SciencesInstitute of VirologyBratislavaSlovakia
  4. 4.Biomedical Research CenterUniversity Hospital Hradec KraloveHradec KraloveCzech Republic

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