Král'ová, M*
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A series of final twelve propanoyloxy derivatives of 5β-cholan-24-oic acid (O-propanoyl derivatives of cholic acid) as potential drug absorption modifiers (skin penetration enhancers, intestinal absorption promoters) was generated by multistep synthesis. Structure confirmation of all generated compounds was accomplished by 1H NMR, 13C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (RM) was determined. The hydrophobicity (log P), solubility (log S), polar surface area (PSA) and molar volume (MV) of the studied compounds were also calculated. All the target compounds were tested for their in vitro transdermal penetration effect and as potential intestinal absorption enhancers. The cytotoxicity of all the evaluated compounds was evaluated against normal human skin fibroblast cells. Their anti-proliferative activity was also assessed against human cancer cell lines: T-lymphoblastic leukemia cell line and breast adenocarcinoma cell line. One compound showed selective cytotoxicity against human skin fibroblast cells and another compound possessed the highest cytotoxicity against all the tested cell lines. Only one compound expressed anti-proliferative effect on leukemia cancer cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC50>37 μM), indicating they would have moderate cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity/polarity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and enhancement effect are discussed in this article.
- MeSH
- buněčná membrána účinky léků metabolismus MeSH
- farmakokinetika MeSH
- hydrofobní a hydrofilní interakce MeSH
- intestinální absorpce účinky léků MeSH
- kožní absorpce účinky léků MeSH
- kyseliny cholové chemie farmakologie toxicita MeSH
- léčivé přípravky metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- permeabilita účinky léků MeSH
- proliferace buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of twenty substituted 2-hydroxy-3-[(2-aryloxyethyl)amino]propyl 4-[(alkoxycarbonyl)amino]benzoates were prepared and characterized. As similar compounds have been described as potential antimycobacterials, primary in vitro screening of the synthesized carbamates was also performed against two mycobacterial species. 2-Hydroxy-3-[2-(2,6-dimethoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride, 2-hydroxy-3-[2-(4-methoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride, and 2-hydroxy-3-[2-(2-methoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride showed higher activity against M. avium subsp. paratuberculosis and M. intracellulare than the standards ciprofloxacin, isoniazid, or pyrazinamide. Cytotoxicity assay of effective compounds was performed using the human monocytic leukaemia THP-1 cell line. Compounds with predicted amphiphilic properties were also tested for their effects on the rate of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. All butyl derivatives significantly stimulated the rate of PET, indicating that the compounds can induce conformational changes in thylakoid membranes resulting in an increase of their permeability and so causing uncoupling of phosphorylation from electron transport.
- MeSH
- antibakteriální látky chemická syntéza farmakologie MeSH
- benzoáty chemická syntéza farmakologie MeSH
- karbamáty chemická syntéza farmakologie MeSH
- Mycobacterium avium subsp. paratuberculosis účinky léků MeSH
- rozpřahující látky chemická syntéza farmakologie MeSH
- Spinacia oleracea účinky léků MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Purine nucleoside phosphorylase (PNP) is a well-known molecular target with potential therapeutic applications in the treatment of T-cell malignancies and/or bacterial/parasitic infections. Here, we report the design, development of synthetic methodology, and biological evaluation of a series of 30 novel PNP inhibitors based on acyclic nucleoside phosphonates bearing a 9-deazahypoxanthine nucleobase. The strongest inhibitors exhibited IC50 values as low as 19 nM (human PNP) and 4 nM (Mycobacterium tuberculosis (Mt) PNP) and highly selective cytotoxicity toward various T-lymphoblastic cell lines with CC50 values as low as 9 nM. No cytotoxic effect was observed on other cancer cell lines (HeLa S3, HL60, HepG2) or primary PBMCs for up to 10 μM. We report the first example of the PNP inhibitor exhibiting over 60-fold selectivity for the pathogenic enzyme (MtPNP) over hPNP. The results are supported by a crystallographic study of eight enzyme-inhibitor complexes and by ADMET profiling in vitro and in vivo.
- MeSH
- inhibitory enzymů * chemie MeSH
- krystalografie MeSH
- lidé MeSH
- purinnukleosidfosforylasa * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pre kvalifikovaný výkon špecializovaných činností sestier a ostatných zdravotníckych pracovníkov, je nevyhnutný všeobecný základ a dobrá orientácia v poznatkoch prírodných a biomedicínskych vied (Král'ová, E., 2006). Do tejto oblasti patria znalosti fyzikálnych princípov zdravotníckej prístrojovej techniky využívanej vo všetkých oblastiach medicíny, tvoriace súčasť sylabu predmetu lekárska fyzika ako aj znalosti fyziologických a patologických mechanizmov v bunkách, orgánoch a celom organizme z pohl'adu lekárskej chémie a biochémie (Bergendi, :C., 2001, 2006). Dóležité sú manuálne zručnosti a pevne zafixované zásady dodržiavania štandardizovaných postupov pri práci s prístrojovou technikou ako aj v laboratórnych postupoch. Podmieňujú správne posúdenie a vyhodnotenie výsledkov, prípadné vylúčenie výskytu artefaktov. Potrebné nástroje pre dosiahnutie uvedených odborných kvalít, teoretických vedomostí, praktických zručností a návykov ponúkajú v rámci vysokoškolského štúdia viaceré základné prírodovedné a podporné predmety napr. lekárska fyzika, rádiológia, lekárska chémia, biochémia, informatika a telemedicína (Kukurová, E. et al., 2006). V príspevku uvádzame výsledky prieskumu výučby uvedených predmetov v študijnom programe ošetrovatel'stvo na vzorke európskych univerzít.
- MeSH
- kurikulum MeSH
- lidé MeSH
- přírodní vědy MeSH
- studium ošetřovatelství vysokoškolské organizace a řízení trendy MeSH
- univerzity MeSH
- vyučování MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Evropa MeSH
