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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F18%3A10380469" target="_blank" >RIV/00179906:_____/18:10380469 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1007/s00044-018-2241-6" target="_blank" >http://dx.doi.org/10.1007/s00044-018-2241-6</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00044-018-2241-6" target="_blank" >10.1007/s00044-018-2241-6</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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&apos;s ability to inhibit Topo I.

Název v anglickém jazyce

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

Popis výsledku anglicky

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&apos;s ability to inhibit Topo I.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Medicinal Chemistry Research

ISSN

1054-2523

e-ISSN

—

Svazek periodika

27

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

2353-2365

Kód UT WoS článku

000444949700011

EID výsledku v databázi Scopus

2-s2.0-85053474137