Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents
Samo za registrovane korisnike
2022
Autori
Hicke, Francisco J.Puerta, Adrián
Dinić, Jelena
Pešić, Milica
Padrón, José M.
López, Óscar
Fernández-Bolaños, José G.
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents. We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondria-directed vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol). Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 μM for 36) to the submicromolar range in most of the cases; this re...presents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269). The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp. Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane. Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon co-administration with a pump-efflux inhibitor.
Ključne reči:
Antiproliferative agents / Chemosensitizer / Mitocans / Mitochondriotropics / Multidrug resistant cells / Phosphonium saltsIzvor:
European Journal of Medicinal Chemistry, 2022, 228, 113980-Izdavač:
- Elsevier
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200007 (Univerzitet u Beogradu, Institut za biološka istraživanja 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
- Spanish Government (PGC2018-094503-B-C22)
- Canary Islands Government (TESIS2020010055)
- COST Action (CA17104 STRATAGEM)
- Junta de Andalucía (FQM134)
- CIN/AEI/10.13039/501100011033 (PID2020-116460RB-I00 )
Napomena:
- Supplementary material: https://cherry.chem.bg.ac.rs/handle/123456789/4870
DOI: 10.1016/j.ejmech.2021.113980
ISSN: 0223-5234
PubMed: 34847410
WoS: 000724271300003
Scopus: 2-s2.0-85119956724
Kolekcije
Institucija/grupa
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Hicke, Francisco J. AU - Puerta, Adrián AU - Dinić, Jelena AU - Pešić, Milica AU - Padrón, José M. AU - López, Óscar AU - Fernández-Bolaños, José G. PY - 2022 UR - http://cherry.chem.bg.ac.rs/handle/123456789/4869 AB - The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents. We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondria-directed vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol). Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 μM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269). The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp. Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane. Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon co-administration with a pump-efflux inhibitor. PB - Elsevier T2 - European Journal of Medicinal Chemistry T1 - Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents VL - 228 SP - 113980 DO - 10.1016/j.ejmech.2021.113980 ER -
@article{ author = "Hicke, Francisco J. and Puerta, Adrián and Dinić, Jelena and Pešić, Milica and Padrón, José M. and López, Óscar and Fernández-Bolaños, José G.", year = "2022", abstract = "The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents. We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondria-directed vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol). Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 μM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269). The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp. Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane. Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon co-administration with a pump-efflux inhibitor.", publisher = "Elsevier", journal = "European Journal of Medicinal Chemistry", title = "Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents", volume = "228", pages = "113980", doi = "10.1016/j.ejmech.2021.113980" }
Hicke, F. J., Puerta, A., Dinić, J., Pešić, M., Padrón, J. M., López, Ó.,& Fernández-Bolaños, J. G.. (2022). Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents. in European Journal of Medicinal Chemistry Elsevier., 228, 113980. https://doi.org/10.1016/j.ejmech.2021.113980
Hicke FJ, Puerta A, Dinić J, Pešić M, Padrón JM, López Ó, Fernández-Bolaños JG. Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents. in European Journal of Medicinal Chemistry. 2022;228:113980. doi:10.1016/j.ejmech.2021.113980 .
Hicke, Francisco J., Puerta, Adrián, Dinić, Jelena, Pešić, Milica, Padrón, José M., López, Óscar, Fernández-Bolaños, José G., "Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents" in European Journal of Medicinal Chemistry, 228 (2022):113980, https://doi.org/10.1016/j.ejmech.2021.113980 . .