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  - Roldán-Peña, Jesús M.
AU  - Puerta, Adrián
AU  - Dinić, Jelena
AU  - Jovanović Stojanov, Sofija
AU  - González-Bakker, Aday
AU  - Hicke, Francisco J.
AU  - Mishra, Atreyee
AU  - Piyasaengthong, Akkharadet
AU  - Maya, Inés
AU  - Walton, James W.
AU  - Pešić, Milica
AU  - Padrón, José M.
AU  - Fernández-Bolaños, José G.
AU  - López, Óscar
PY  - 2023
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0045206823000706
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5487
AB  - Most of the currently available cytotoxic agents for tackling cancer are devoid of selectivity, thus causing severe side-effects. This situation stimulated us to develop new antiproliferative agents with enhanced affinity towards tumour cells. We focused our attention on novel chalcogen-containing compounds (thiosemicarbazones, disulfides, selenoureas, thio- and selenocyanates), and particularly on selenium derivatives, as it has been documented that this kind of compounds might act as prodrugs releasing selenium-based reactive species on tumour cells. Particularly interesting in terms of potency and selectivity was a pharmacophore comprised by a selenocyanato-alkyl fragment connected to a p-phenylenediamine residue, where the nature of the second amino moiety (free, Boc-protected, enamine-protected) provided a wide variety of antiproliferative activities, ranging from the low micromolar to the nanomolar values. The optimized structure was in turn conjugated through a peptide linkage with biotin (vitamin B7), a cellular growth promoter, whose receptor is overexpressed in numerous cancer cells; the purpose was to develop a selective vector towards malignant cells. Such biotinylated derivative behaved as a very strong antiproliferative agent, achieving GI50 values in the low nM range for most of the tested cancer cells; moreover, it was featured with an outstanding selectivity, with GI50 > 100 µM against human fibroblasts. Mechanistic studies on the mode of inhibition of the biotinylated selenocyanate revealed (Annexin-V assay) a remarkable increase in the number of apoptotic cells compared to the control experiment; moreover, depolarization of the mitochondrial membrane was detected by flow cytometry analysis, and with fluorescent microscopy, what supports the apoptotic cell death. Prior to the apoptotic events, cytostatic effects were observed against SW1573 cells using label-free cell-living imaging; therefore, tumour cell division was prevented. Multidrug resistant cell lines exhibited a reduced sensitivity towards the biotinylated selenocyanate, probably due to its P-gp-mediated efflux. Remarkably, antiproliferative levels could be restored by co-administration with tariquidar, a P-gp inhibitor; this approach can, therefore, overcome multidrug resistance mediated by the P-gp efflux system.
PB  - Academic Press Inc.
T2  - Bioorganic Chemistry
T1  - Biotinylated selenocyanates: Potent and selective cytostatic agents
VL  - 133
DO  - 10.1016/j.bioorg.2023.106410
SP  - 106410
ER  - 

@article{
author = "Roldán-Peña, Jesús M. and Puerta, Adrián and Dinić, Jelena and Jovanović Stojanov, Sofija and González-Bakker, Aday and Hicke, Francisco J. and Mishra, Atreyee and Piyasaengthong, Akkharadet and Maya, Inés and Walton, James W. and Pešić, Milica and Padrón, José M. and Fernández-Bolaños, José G. and López, Óscar",
year = "2023",
abstract = "Most of the currently available cytotoxic agents for tackling cancer are devoid of selectivity, thus causing severe side-effects. This situation stimulated us to develop new antiproliferative agents with enhanced affinity towards tumour cells. We focused our attention on novel chalcogen-containing compounds (thiosemicarbazones, disulfides, selenoureas, thio- and selenocyanates), and particularly on selenium derivatives, as it has been documented that this kind of compounds might act as prodrugs releasing selenium-based reactive species on tumour cells. Particularly interesting in terms of potency and selectivity was a pharmacophore comprised by a selenocyanato-alkyl fragment connected to a p-phenylenediamine residue, where the nature of the second amino moiety (free, Boc-protected, enamine-protected) provided a wide variety of antiproliferative activities, ranging from the low micromolar to the nanomolar values. The optimized structure was in turn conjugated through a peptide linkage with biotin (vitamin B7), a cellular growth promoter, whose receptor is overexpressed in numerous cancer cells; the purpose was to develop a selective vector towards malignant cells. Such biotinylated derivative behaved as a very strong antiproliferative agent, achieving GI50 values in the low nM range for most of the tested cancer cells; moreover, it was featured with an outstanding selectivity, with GI50 > 100 µM against human fibroblasts. Mechanistic studies on the mode of inhibition of the biotinylated selenocyanate revealed (Annexin-V assay) a remarkable increase in the number of apoptotic cells compared to the control experiment; moreover, depolarization of the mitochondrial membrane was detected by flow cytometry analysis, and with fluorescent microscopy, what supports the apoptotic cell death. Prior to the apoptotic events, cytostatic effects were observed against SW1573 cells using label-free cell-living imaging; therefore, tumour cell division was prevented. Multidrug resistant cell lines exhibited a reduced sensitivity towards the biotinylated selenocyanate, probably due to its P-gp-mediated efflux. Remarkably, antiproliferative levels could be restored by co-administration with tariquidar, a P-gp inhibitor; this approach can, therefore, overcome multidrug resistance mediated by the P-gp efflux system.",
publisher = "Academic Press Inc.",
journal = "Bioorganic Chemistry",
title = "Biotinylated selenocyanates: Potent and selective cytostatic agents",
volume = "133",
doi = "10.1016/j.bioorg.2023.106410",
pages = "106410"
}

Roldán-Peña, J. M., Puerta, A., Dinić, J., Jovanović Stojanov, S., González-Bakker, A., Hicke, F. J., Mishra, A., Piyasaengthong, A., Maya, I., Walton, J. W., Pešić, M., Padrón, J. M., Fernández-Bolaños, J. G.,& López, Ó.. (2023). Biotinylated selenocyanates: Potent and selective cytostatic agents. in Bioorganic Chemistry
Academic Press Inc.., 133, 106410.
https://doi.org/10.1016/j.bioorg.2023.106410

Roldán-Peña JM, Puerta A, Dinić J, Jovanović Stojanov S, González-Bakker A, Hicke FJ, Mishra A, Piyasaengthong A, Maya I, Walton JW, Pešić M, Padrón JM, Fernández-Bolaños JG, López Ó. Biotinylated selenocyanates: Potent and selective cytostatic agents. in Bioorganic Chemistry. 2023;133:106410.
doi:10.1016/j.bioorg.2023.106410 .

Roldán-Peña, Jesús M., Puerta, Adrián, Dinić, Jelena, Jovanović Stojanov, Sofija, González-Bakker, Aday, Hicke, Francisco J., Mishra, Atreyee, Piyasaengthong, Akkharadet, Maya, Inés, Walton, James W., Pešić, Milica, Padrón, José M., Fernández-Bolaños, José G., López, Óscar, "Biotinylated selenocyanates: Potent and selective cytostatic agents" in Bioorganic Chemistry, 133 (2023):106410,
https://doi.org/10.1016/j.bioorg.2023.106410 . .