التفاصيل البيبلوغرافية
| العنوان: |
Frentizole derivatives with mTOR inhibiting and senomorphic properties. |
| المؤلفون: |
Chrienova, Zofia1 (AUTHOR), Rysanek, David1,2 (AUTHOR), Novak, Josef2 (AUTHOR), Vasicova, Pavla2 (AUTHOR), Oleksak, Patrik1 (AUTHOR), Andrys, Rudolf1 (AUTHOR), Skarka, Adam1 (AUTHOR), Dumanovic, Jelena3 (AUTHOR), Milovanovic, Zoran4 (AUTHOR), Jacevic, Vesna5 (AUTHOR), Chvojkova, Marketa1,6 (AUTHOR), Holubova, Kristina1,6 (AUTHOR), Vales, Karel1,6,7 (AUTHOR), Skoupilova, Veronika1 (AUTHOR), Valko, Marian8 (AUTHOR), Jomova, Klaudia9 (AUTHOR), Alomar, Suliman Y.10 (AUTHOR), Botelho, Fernanda D.11 (AUTHOR), Franca, Tanos C.C.1,11 (AUTHOR), Kuca, Kamil1 (AUTHOR) |
| المصدر: |
Biomedicine & Pharmacotherapy. Nov2023, Vol. 167, pN.PAG-N.PAG. 1p. |
| مصطلحات موضوعية: |
*FREE radicals, *ALZHEIMER'S disease, *ACUTE toxicity testing, *ALCOHOL dehydrogenase, *IMMUNOSUPPRESSIVE agents, *MTOR inhibitors |
| مستخلص: |
Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole´s potential to disrupt toxic amyloid β (A β) - A β -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 A β -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 (LD 50 in male mice 559 mg/kg; LD 50 in female mice 575 mg/kg). [Display omitted] • The most studied anti-aging drug is mTOR inhibitor – rapamycin. • Another theory explaining aging is based on excessive free radical production in mitochondria. • Presented compounds (1 – 9) combine both theories (mTOR- and free radical-centric theories). • 1 – 9 showed cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence effects. • 4 proved to be relatively safe within the test of acute toxicity with the ability to cross the BBB. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
Academic Search Index |
Full Text Finder