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in vitro and in silico Studies of Interaction of Synthetic 2,6,9-Trisubstituted Purine Kinase Inhibitors BPA-302, BP-21 and BP-117 With Liver Drug-Metabolizing Cytochromes P450

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F20%3A00541026" target="_blank" >RIV/61389030:_____/20:00541026 - isvavai.cz</a>

  • Nalezeny alternativní kódy

    RIV/61989592:15110/20:73603436

  • Výsledek na webu

    <a href="https://www.biomed.cas.cz/physiolres/pdf/2020/69_S627.pdf" target="_blank" >https://www.biomed.cas.cz/physiolres/pdf/2020/69_S627.pdf</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.33549/physiolres.934611" target="_blank" >10.33549/physiolres.934611</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    in vitro and in silico Studies of Interaction of Synthetic 2,6,9-Trisubstituted Purine Kinase Inhibitors BPA-302, BP-21 and BP-117 With Liver Drug-Metabolizing Cytochromes P450

  • Popis výsledku v původním jazyce

    An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Here, emphasis is placed on interactions of these compounds with the nine most important forms of CYP to evaluate the possibility of inhibition of these enzymes. The possibility of their inhibitory effect was studied in vitro on selected human liver microsomal CYP enzymes. The most affected enzyme was CYP2C19. Its activity dropped to 22 % of its original value by BPA-302, to 13 % by BP-21 and to 6 % by BP-117 at the highest concentration tested (250 mu mol.l(-1)). The results suggest that the metabolism of concomitantly administered drugs should not be significantly affected at lower doses. Molecular docking of BPA-302 indicated that it can bind to active site of both CYP2C19 and CYP2D6 enzymes above the heme cofactor corroborating the experimental data.

  • Název v anglickém jazyce

    in vitro and in silico Studies of Interaction of Synthetic 2,6,9-Trisubstituted Purine Kinase Inhibitors BPA-302, BP-21 and BP-117 With Liver Drug-Metabolizing Cytochromes P450

  • Popis výsledku anglicky

    An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Here, emphasis is placed on interactions of these compounds with the nine most important forms of CYP to evaluate the possibility of inhibition of these enzymes. The possibility of their inhibitory effect was studied in vitro on selected human liver microsomal CYP enzymes. The most affected enzyme was CYP2C19. Its activity dropped to 22 % of its original value by BPA-302, to 13 % by BP-21 and to 6 % by BP-117 at the highest concentration tested (250 mu mol.l(-1)). The results suggest that the metabolism of concomitantly administered drugs should not be significantly affected at lower doses. Molecular docking of BPA-302 indicated that it can bind to active site of both CYP2C19 and CYP2D6 enzymes above the heme cofactor corroborating the experimental data.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    10401 - Organic chemistry

Návaznosti výsledku

  • Projekt

  • Návaznosti

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Ostatní

  • Rok uplatnění

    2020

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Physiological Research

  • ISSN

    0862-8408

  • e-ISSN

    1802-9973

  • Svazek periodika

    69

  • Číslo periodika v rámci svazku

    SEP

  • Stát vydavatele periodika

    CZ - Česká republika

  • Počet stran výsledku

    10

  • Strana od-do

    627-636

  • Kód UT WoS článku

    000621838200009

  • EID výsledku v databázi Scopus

    2-s2.0-85102232304