Intracellular distribution of new tacrine analogues as a potential cause of their cytotoxicity against human neuroblastoma cells SH-SY5Y
- 116 Downloads
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.
KeywordsGlyco-tacrine conjugates Tacrine Acetylcholinesterase inhibitors DNA SH-SY5Y cells
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.
- Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 1:CD005593Google Scholar
- Bolognesi ML, Cavalli A, Valgimigli L, Bartolini M, Rosini M, Andrisano V, Recanatini M, Melchiorre C (2007) Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer’s disease. J Med Chem 50:6446–6449CrossRefGoogle Scholar
- Busa J (2006) Octave. Technical University in Košice, KošiceGoogle Scholar
- Camps P, Formosa X, Galdeano C, Gómez T, Muñoz-Torrero D, Ramírez L, Viayna E, Gómez E, Isambert N, Lavilla, Badia A, Clos MV, Bartolini M, Mancini F, Andrisano V, Bidon-Chanal A, Huertas O, Dafni T, Luque FJ (2010) Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates. Chem Biol Interact 187:411–5CrossRefGoogle Scholar
- Da Costa JS, Lopes JPB, Russowsky D, Petzhold CL, Borges ACDA, Ceschi MA, Konrath E, Batassini C, Lunardi PS, Gonçalves CAS (2013) Synthesis of tacrine–lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors. Eur J Med Chem 62:556–563CrossRefGoogle Scholar
- Galdeano C, Viayna E, Sola I, Formosa X, Camps P, Badia A, Clos MV, Relat J, Ratia M, Bartolini M, Mancini F, Andrisano V, Salmona M, Minguillón C, González-Muñoz GC, Rodríguez-Franco MI, Bidon-Chanal A, Luque FJ, Muñoz-Torrero D (2012) Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer’s and prion diseases. J Med Chem 55:661–669CrossRefGoogle Scholar
- Janočková J, Plsikova J, Kašpárková J, Brabec V, Jendželovský R, Mikes J, Koval J, Hamulaková S, Fedoročko P, Kuča K, Kozurkova M (2015) Inhibition of DNA topoisomerases I and II and growth inhibition of HL-60 cells by novel acridine-based compounds. Eur J Med Chem 76:192–202Google Scholar
- Marco-Contelles J, León R, de los Ríos C, Samadi A, Bartolini M, Andrisano V, Huertas O, Barril X, Luque FJ, Rodríguez-Franco MI, López B, López MG, García AG, Carreiras Mdo C, Villarroya M (2009) Tacripyrines, the first tacrine–dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease. J Med Chem 52:2724–2732CrossRefGoogle Scholar
- Minarini A, Milelli A, Tumiatti V, Rosini M, Simoni E, Bolognesi ML, Andrisano V, Bartolini M, Motori E, Angeloni C, Hrelia S (2012) Cystamine–tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer’s disease treatment. Neuropharmacology 62:997–1003CrossRefGoogle Scholar
- Rosini M, Simoni E, Bartolini M, Cavalli A, Ceccarini L, Pascu N, McClymont DW, Tarozzi A, Bolognesi ML, Minarini A, Tumiatti V, Andrisano V, Mellor IR, Melchiorre C (2008) Inhibition of acetylcholinesterase, beta-amyloid aggregation, and NMDA receptors in Alzheimer’s disease: a promising direction for the multi-target-directed ligands gold rush. J Med Chem 51:4381–4384CrossRefGoogle Scholar
- Rzesturski W, Ledochowski Z (1963) Synthese neuer potentiellen antitumor- substanzen. XX. Derivaten des 9-methyl-acridine. II. Über die synthese des 9-aminomethyl-acridines. Ann Soc Chim Pol 37:1631–1633Google Scholar