TY  - JOUR
AU  - Fuentes-Aguilar, Alma
AU  - González-Bakker, Aday
AU  - Jovanović, Mirna
AU  - Jovanović Stojanov, Sofija
AU  - Puerta, Adrián
AU  - Gargano, Adriana
AU  - Dinić, Jelena
AU  - Vega-Báez, José L.
AU  - Merino-Montiel, Penélope
AU  - Montiel-Smith, Sara
AU  - Alcaro, Stefano
AU  - Nocentini, Alessio
AU  - Pešić, Milica
AU  - Supuran, Claudiu T.
AU  - Padrón, José M.
AU  - Fernández-Bolaños, José G.
AU  - López, Óscar
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6550
AB  - Being aware of the need to develop more efficient therapies against cancer, herein we disclose an innovative
approach for the design of selective antiproliferative agents. We have accomplished the conjugation of a
coumarin fragment with lipophilic cations (triphenylphosphonium salts, guanidinium) for providing mitochondriotropic
agents that simultaneously target also carbonic anhydrases IX and XII, involved in the development
and progression of cancer. The new compounds prepared herein turned out to be strong inhibitors of
carbonic anhydrases IX and XII of human origin (low-to-mid nM range), also endowed with high selectivity,
exhibiting negligible activity towards cytosolic CA isoforms. Key interactions with the enzyme were analysed
using docking and molecular dynamics simulations.
Regarding their in vitro antiproliferative activities, an increase of the tether length connecting both pharmacophores
led to a clear improvement in potency, reaching the submicromolar range for the lead compounds, and
an outstanding selectivity towards tumour cell lines (S.I. up to >357). Cytotoxic effects were also analysed on
MDR cell lines under hypoxic and normoxic conditions. Chemoresistance exhibited by phosphonium salts, and
not by guanidines, against MDR cells was based on the fact that the former were found to be substrates of Pglycoprotein
(P-gp), the pump responsible for extruding foreign chemicals; this situation was reversed by
administrating tariquidar, a third generation P-gp inhibitor. Moreover, phosphonium salts provoked a profound
depolarization of mitochondria membranes from tumour cells, thus probably compromising their oxidative
metabolism.
To gain insight into the mode of action of title compounds, continuous live cell microscopy was employed;
interestingly, this technique revealed two different antiproliferative mechanisms for both families of mitocans.
Whereas phosphonium salts had a cytostatic effect, blocking cell division, guanidines led to cell death via
apoptosis.
PB  - Elsevier Inc.
T2  - Bioorganic Chemistry
T1  - Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases
VL  - 145
DO  - 10.1016/j.bioorg.2024.107168
SP  - 107168
ER  - 

@article{
author = "Fuentes-Aguilar, Alma and González-Bakker, Aday and Jovanović, Mirna and Jovanović Stojanov, Sofija and Puerta, Adrián and Gargano, Adriana and Dinić, Jelena and Vega-Báez, José L. and Merino-Montiel, Penélope and Montiel-Smith, Sara and Alcaro, Stefano and Nocentini, Alessio and Pešić, Milica and Supuran, Claudiu T. and Padrón, José M. and Fernández-Bolaños, José G. and López, Óscar",
year = "2024",
abstract = "Being aware of the need to develop more efficient therapies against cancer, herein we disclose an innovative
approach for the design of selective antiproliferative agents. We have accomplished the conjugation of a
coumarin fragment with lipophilic cations (triphenylphosphonium salts, guanidinium) for providing mitochondriotropic
agents that simultaneously target also carbonic anhydrases IX and XII, involved in the development
and progression of cancer. The new compounds prepared herein turned out to be strong inhibitors of
carbonic anhydrases IX and XII of human origin (low-to-mid nM range), also endowed with high selectivity,
exhibiting negligible activity towards cytosolic CA isoforms. Key interactions with the enzyme were analysed
using docking and molecular dynamics simulations.
Regarding their in vitro antiproliferative activities, an increase of the tether length connecting both pharmacophores
led to a clear improvement in potency, reaching the submicromolar range for the lead compounds, and
an outstanding selectivity towards tumour cell lines (S.I. up to >357). Cytotoxic effects were also analysed on
MDR cell lines under hypoxic and normoxic conditions. Chemoresistance exhibited by phosphonium salts, and
not by guanidines, against MDR cells was based on the fact that the former were found to be substrates of Pglycoprotein
(P-gp), the pump responsible for extruding foreign chemicals; this situation was reversed by
administrating tariquidar, a third generation P-gp inhibitor. Moreover, phosphonium salts provoked a profound
depolarization of mitochondria membranes from tumour cells, thus probably compromising their oxidative
metabolism.
To gain insight into the mode of action of title compounds, continuous live cell microscopy was employed;
interestingly, this technique revealed two different antiproliferative mechanisms for both families of mitocans.
Whereas phosphonium salts had a cytostatic effect, blocking cell division, guanidines led to cell death via
apoptosis.",
publisher = "Elsevier Inc.",
journal = "Bioorganic Chemistry",
title = "Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases",
volume = "145",
doi = "10.1016/j.bioorg.2024.107168",
pages = "107168"
}

Fuentes-Aguilar, A., González-Bakker, A., Jovanović, M., Jovanović Stojanov, S., Puerta, A., Gargano, A., Dinić, J., Vega-Báez, J. L., Merino-Montiel, P., Montiel-Smith, S., Alcaro, S., Nocentini, A., Pešić, M., Supuran, C. T., Padrón, J. M., Fernández-Bolaños, J. G.,& López, Ó.. (2024). Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases. in Bioorganic Chemistry
Elsevier Inc.., 145, 107168.
https://doi.org/10.1016/j.bioorg.2024.107168

Fuentes-Aguilar A, González-Bakker A, Jovanović M, Jovanović Stojanov S, Puerta A, Gargano A, Dinić J, Vega-Báez JL, Merino-Montiel P, Montiel-Smith S, Alcaro S, Nocentini A, Pešić M, Supuran CT, Padrón JM, Fernández-Bolaños JG, López Ó. Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases. in Bioorganic Chemistry. 2024;145:107168.
doi:10.1016/j.bioorg.2024.107168 .

Fuentes-Aguilar, Alma, González-Bakker, Aday, Jovanović, Mirna, Jovanović Stojanov, Sofija, Puerta, Adrián, Gargano, Adriana, Dinić, Jelena, Vega-Báez, José L., Merino-Montiel, Penélope, Montiel-Smith, Sara, Alcaro, Stefano, Nocentini, Alessio, Pešić, Milica, Supuran, Claudiu T., Padrón, José M., Fernández-Bolaños, José G., López, Óscar, "Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases" in Bioorganic Chemistry, 145 (2024):107168,
https://doi.org/10.1016/j.bioorg.2024.107168 . .

TY  - JOUR
AU  - Hicke, Francisco
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://radar.ibiss.bg.ac.rs/handle/123456789/4671
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  - Amsterdam : Elsevier Ltd
T2  - European Journal of Medicinal Chemistry
T1  - Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents
VL  - 228
DO  - 10.1016/j.ejmech.2021.113980
SP  - 113980
ER  - 

@article{
author = "Hicke, Francisco 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 = "Amsterdam : Elsevier Ltd",
journal = "European Journal of Medicinal Chemistry",
title = "Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents",
volume = "228",
doi = "10.1016/j.ejmech.2021.113980",
pages = "113980"
}

Hicke, F., 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
Amsterdam : Elsevier Ltd., 228, 113980.
https://doi.org/10.1016/j.ejmech.2021.113980

Hicke F, 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, 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 . .