New glycoconjugation strategies for Ruthenium(II) arene complexes via phosphane ligands and assessment of their antiproliferative activity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15640%2F22%3A73617076" target="_blank" >RIV/61989592:15640/22:73617076 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0045206822003066?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0045206822003066?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bioorg.2022.105901" target="_blank" >10.1016/j.bioorg.2022.105901</a>

Jazyk výsledku

angličtina

Název v původním jazyce

New glycoconjugation strategies for Ruthenium(II) arene complexes via phosphane ligands and assessment of their antiproliferative activity

Popis výsledku v původním jazyce

Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, D-galactal and D-allal-derived vinyl epoxides (VE beta and VE alpha) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1 beta and 1 alpha. Ligand exchange with [Ru(C2O4)(eta(6)-p-cymene)(H2O)] gave the glycoconjugated complexes Ru1 beta and Ru1 alpha which were subsequently dihydroxylated with OsO4/N-methylmorpholine N-oxide to Ru2 beta and Ru2 alpha containing O-benzyl D-mannose and D-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-beta-D-gluco-pyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3 center dot BH3. Zemplen deacylation with MeONa/MeOH gave the deprotected D-glucopyranoside derivative 4 center dot BH3. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3 center dot BH3 and 4 center dot BH3 with [Ru(C2O4)(eta(6)-p-cymene)(H2O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1 beta, Ru1 alpha). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the beta anomer. However, Ru1 beta, Ru1 alpha did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1 beta, inducing cell death by apoptosis.

Název v anglickém jazyce

New glycoconjugation strategies for Ruthenium(II) arene complexes via phosphane ligands and assessment of their antiproliferative activity

Popis výsledku anglicky

Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, D-galactal and D-allal-derived vinyl epoxides (VE beta and VE alpha) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1 beta and 1 alpha. Ligand exchange with [Ru(C2O4)(eta(6)-p-cymene)(H2O)] gave the glycoconjugated complexes Ru1 beta and Ru1 alpha which were subsequently dihydroxylated with OsO4/N-methylmorpholine N-oxide to Ru2 beta and Ru2 alpha containing O-benzyl D-mannose and D-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-beta-D-gluco-pyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3 center dot BH3. Zemplen deacylation with MeONa/MeOH gave the deprotected D-glucopyranoside derivative 4 center dot BH3. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3 center dot BH3 and 4 center dot BH3 with [Ru(C2O4)(eta(6)-p-cymene)(H2O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1 beta, Ru1 alpha). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the beta anomer. However, Ru1 beta, Ru1 alpha did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1 beta, inducing cell death by apoptosis.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10402 - Inorganic and nuclear chemistry

Projekt

<a href="/cs/project/EF16_019%2F0000754" target="_blank" >EF16_019/0000754: Nanotechnologie pro budoucnost</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

BIOORGANIC CHEMISTRY

ISSN

0045-2068

e-ISSN

1090-2120

Svazek periodika

126

Číslo periodika v rámci svazku

September

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

nestrankovano

Kód UT WoS článku

000833463700003

EID výsledku v databázi Scopus

2-s2.0-85131454851