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Frentizole derivatives with mTOR inhibiting and senomorphic properties

Z. Chrienova, D. Rysanek, J. Novak, P. Vasicova, P. Oleksak, R. Andrys, A. Skarka, J. Dumanovic, Z. Milovanovic, V. Jacevic, M. Chvojkova, K. Holubova, K. Vales, V. Skoupilova, M. Valko, K. Jomova, SY. Alomar, FD. Botelho, TCC. Franca, K. Kuca,...

. 2023 ; 167 (-) : 115600. [pub] 20230930

Jazyk angličtina Země Francie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24000825

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).

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$a Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole ́s potential to disrupt toxic amyloid β (Aβ) - Aβ-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer ́s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor - rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aβ-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 - 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD50 in male mice 559 mg/kg; LD50 in female mice 575 mg/kg).
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$a Rysanek, David $u Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic
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$a Novak, Josef $u Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic
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$a Vasicova, Pavla $u Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic
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$a Oleksak, Patrik $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic
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$a Andrys, Rudolf $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic
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$a Skarka, Adam $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic
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$a Dumanovic, Jelena $u Faculty of Chemistry, University of Belgrade, Studenski trg 16, 11000 Belgrade, Serbia
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$a Milovanovic, Zoran $u Special Police Unit, Ministry of Interior, Trebevićka 12/A, 11030 Belgrade, Serbia
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$a Jacevic, Vesna $u Department of Experimental Toxicology and Pharmacology, National Poison Control Centre, Military Medical Academy & Medical Faculty of the Military Medical Academy, University of Defence, 11 Crnotravska, 11000 Belgrade, Serbia
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$a Chvojkova, Marketa $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic; National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic
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$a Holubova, Kristina $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic; National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic
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$a Vales, Karel $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic; National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic; Third Faculty of Medicine, Charles University, Ruska 87, 100 00 Prague 10, Czech Republic
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$a Skoupilova, Veronika $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic
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$a Valko, Marian $u Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, 812 37 Bratislava, Slovakia
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$a Jomova, Klaudia $u Department of Chemistry, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 01 Nitra, Slovakia
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$a Alomar, Suliman Y $u Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
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$a Botelho, Fernanda D $u Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMCBD), Military Institute of Engineering, 22290-270 Rio de Janeiro, RJ, Brazil
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$a Franca, Tanos C C $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic; Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMCBD), Military Institute of Engineering, 22290-270 Rio de Janeiro, RJ, Brazil
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$a Kuca, Kamil $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic
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$a Hodny, Zdenek $u Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic. Electronic address: zdenek.hodny@img.cas.cz
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$a Nepovimova, Eugenie $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic. Electronic address: eugenie.nepovimova@uhk.cz
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