TY  - JOUR
AU  - Chrienova, Zofia
AU  - Rysanek, David
AU  - Novak, Josef
AU  - Vasicova, Pavla
AU  - Oleksak, Patrik
AU  - Andrys, Rudolf
AU  - Skarka, Adam
AU  - Dumanović, Jelena
AU  - Milovanović, Zoran
AU  - Jaćević, Vesna
AU  - Chvojkova, Marketa
AU  - Holubova, Kristina
AU  - Vales, Karel
AU  - Skoupilova, Veronika
AU  - Valko, Marian
AU  - Jomova, Klaudia
AU  - Alomar, Suliman Y.
AU  - Botelho, Fernanda D.
AU  - Franca, Tanos C. C.
AU  - Kuca, Kamil
AU  - Hodny, Zdenek
AU  - Nepovimova, Eugenie
PY  - 2023
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/6376
AB  - Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole´s potential to disrupt toxic amyloid β (Aβ) - Aβ-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer´s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor – rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aβ-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 – 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD50 in male mice 559 mg/kg; LD50 in female mice 575 mg/kg).
PB  - Elsevier
T2  - Biomedicine & Pharmacotherapy
T1  - Frentizole derivatives with mTOR inhibiting and senomorphic properties
VL  - 167
SP  - 115600
DO  - 10.1016/j.biopha.2023.115600
ER  - 

@article{
author = "Chrienova, Zofia and Rysanek, David and Novak, Josef and Vasicova, Pavla and Oleksak, Patrik and Andrys, Rudolf and Skarka, Adam and Dumanović, Jelena and Milovanović, Zoran and Jaćević, Vesna and Chvojkova, Marketa and Holubova, Kristina and Vales, Karel and Skoupilova, Veronika and Valko, Marian and Jomova, Klaudia and Alomar, Suliman Y. and Botelho, Fernanda D. and Franca, Tanos C. C. and Kuca, Kamil and Hodny, Zdenek and Nepovimova, Eugenie",
year = "2023",
abstract = "Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole´s potential to disrupt toxic amyloid β (Aβ) - Aβ-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer´s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor – rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aβ-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 – 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD50 in male mice 559 mg/kg; LD50 in female mice 575 mg/kg).",
publisher = "Elsevier",
journal = "Biomedicine & Pharmacotherapy",
title = "Frentizole derivatives with mTOR inhibiting and senomorphic properties",
volume = "167",
pages = "115600",
doi = "10.1016/j.biopha.2023.115600"
}

Chrienova, Z., Rysanek, D., Novak, J., Vasicova, P., Oleksak, P., Andrys, R., Skarka, A., Dumanović, J., Milovanović, Z., Jaćević, V., Chvojkova, M., Holubova, K., Vales, K., Skoupilova, V., Valko, M., Jomova, K., Alomar, S. Y., Botelho, F. D., Franca, T. C. C., Kuca, K., Hodny, Z.,& Nepovimova, E.. (2023). Frentizole derivatives with mTOR inhibiting and senomorphic properties. in Biomedicine & Pharmacotherapy
Elsevier., 167, 115600.
https://doi.org/10.1016/j.biopha.2023.115600

Chrienova Z, Rysanek D, Novak J, Vasicova P, Oleksak P, Andrys R, Skarka A, Dumanović J, Milovanović Z, Jaćević V, Chvojkova M, Holubova K, Vales K, Skoupilova V, Valko M, Jomova K, Alomar SY, Botelho FD, Franca TCC, Kuca K, Hodny Z, Nepovimova E. Frentizole derivatives with mTOR inhibiting and senomorphic properties. in Biomedicine & Pharmacotherapy. 2023;167:115600.
doi:10.1016/j.biopha.2023.115600 .

Chrienova, Zofia, Rysanek, David, Novak, Josef, Vasicova, Pavla, Oleksak, Patrik, Andrys, Rudolf, Skarka, Adam, Dumanović, Jelena, Milovanović, Zoran, Jaćević, Vesna, Chvojkova, Marketa, Holubova, Kristina, Vales, Karel, Skoupilova, Veronika, Valko, Marian, Jomova, Klaudia, Alomar, Suliman Y., Botelho, Fernanda D., Franca, Tanos C. C., Kuca, Kamil, Hodny, Zdenek, Nepovimova, Eugenie, "Frentizole derivatives with mTOR inhibiting and senomorphic properties" in Biomedicine & Pharmacotherapy, 167 (2023):115600,
https://doi.org/10.1016/j.biopha.2023.115600 . .