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 . .

TY  - JOUR
AU  - Alov, Petko
AU  - Al Sharif, Merilin
AU  - Aluani, Denitsa
AU  - Chegaev, Konstantin
AU  - Dinić, Jelena
AU  - Divac Rankov, Aleksandra
AU  - Fernandes, Miguel X.
AU  - Fusi, Fabio
AU  - García-Sosa, Alfonso T.
AU  - Juvonen, Risto
AU  - Kondeva-Burdina, Magdalena
AU  - Padrón, José M.
AU  - Pajeva, Ilza
AU  - Pencheva, Tania
AU  - Puerta, Adrián
AU  - Raunio, Hannu
AU  - Riganti, Chiara
AU  - Tsakovska, Ivanka
AU  - Tzankova, Virginia
AU  - Yordanov, Yordan
AU  - Saponara, Simona
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4870
AB  - Sdox is a hydrogen sulfide (H2S)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary in silico, in vitro, and in vivo approach. Doxorubicin was used as the reference compound. The in silico profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. In vitro data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings.
PB  - Lausanne : Frontiers Media
T2  - Frontiers in Pharmacology
T1  - A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors
VL  - 13
DO  - 10.3389/fphar.2022.831791
SP  - 831791
ER  - 

@article{
author = "Alov, Petko and Al Sharif, Merilin and Aluani, Denitsa and Chegaev, Konstantin and Dinić, Jelena and Divac Rankov, Aleksandra and Fernandes, Miguel X. and Fusi, Fabio and García-Sosa, Alfonso T. and Juvonen, Risto and Kondeva-Burdina, Magdalena and Padrón, José M. and Pajeva, Ilza and Pencheva, Tania and Puerta, Adrián and Raunio, Hannu and Riganti, Chiara and Tsakovska, Ivanka and Tzankova, Virginia and Yordanov, Yordan and Saponara, Simona",
year = "2022",
abstract = "Sdox is a hydrogen sulfide (H2S)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary in silico, in vitro, and in vivo approach. Doxorubicin was used as the reference compound. The in silico profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. In vitro data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings.",
publisher = "Lausanne : Frontiers Media",
journal = "Frontiers in Pharmacology",
title = "A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors",
volume = "13",
doi = "10.3389/fphar.2022.831791",
pages = "831791"
}

Alov, P., Al Sharif, M., Aluani, D., Chegaev, K., Dinić, J., Divac Rankov, A., Fernandes, M. X., Fusi, F., García-Sosa, A. T., Juvonen, R., Kondeva-Burdina, M., Padrón, J. M., Pajeva, I., Pencheva, T., Puerta, A., Raunio, H., Riganti, C., Tsakovska, I., Tzankova, V., Yordanov, Y.,& Saponara, S.. (2022). A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors. in Frontiers in Pharmacology
Lausanne : Frontiers Media., 13, 831791.
https://doi.org/10.3389/fphar.2022.831791

Alov P, Al Sharif M, Aluani D, Chegaev K, Dinić J, Divac Rankov A, Fernandes MX, Fusi F, García-Sosa AT, Juvonen R, Kondeva-Burdina M, Padrón JM, Pajeva I, Pencheva T, Puerta A, Raunio H, Riganti C, Tsakovska I, Tzankova V, Yordanov Y, Saponara S. A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors. in Frontiers in Pharmacology. 2022;13:831791.
doi:10.3389/fphar.2022.831791 .

Alov, Petko, Al Sharif, Merilin, Aluani, Denitsa, Chegaev, Konstantin, Dinić, Jelena, Divac Rankov, Aleksandra, Fernandes, Miguel X., Fusi, Fabio, García-Sosa, Alfonso T., Juvonen, Risto, Kondeva-Burdina, Magdalena, Padrón, José M., Pajeva, Ilza, Pencheva, Tania, Puerta, Adrián, Raunio, Hannu, Riganti, Chiara, Tsakovska, Ivanka, Tzankova, Virginia, Yordanov, Yordan, Saponara, Simona, "A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors" in Frontiers in Pharmacology, 13 (2022):831791,
https://doi.org/10.3389/fphar.2022.831791 . .

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 . .