Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico density functional theory calculations suggested graviquinone as a kinetic product of pcm-scavenging •OH radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.
- MeSH
- antitumorózní látky farmakologie toxicita MeSH
- chemorezistence účinky léků MeSH
- cyklohexanony farmakologie toxicita MeSH
- hydroxylový radikál chemie MeSH
- kyseliny kumarové chemie metabolismus farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- objevování léků MeSH
- oxidace-redukce MeSH
- počítačová simulace MeSH
- poškození DNA účinky léků MeSH
- scavengery volných radikálů farmakologie toxicita MeSH
- signální transdukce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Scadoxus puniceus (Amaryllidaceae), a medicinal plant of high value in South Africa, is used as a component of a traditional herbal tonic prescribed to treat several ailments. Ultra-high performance liquid chromatography-tandem mass spectrometry quantified the phenolic compounds in different organs of S. puniceus. Gravity column chromatography was used to separate fractions and active compounds. The structure of these compounds was determined using 1D and 2D nuclear magnetic resonance and mass spectroscopic techniques. A microplate technique was used to determine the acetylcholinesterase inhibitory activity of the pure compounds. Metabolite profiling revealed a greater profusion of hydroxycinnamic acids (69.5%), as opposed to hydroxybenzoic acids (30.5%). Chlorogenic acid was the most abundant (49.6% of hydroxycinnamic acids) compound. In addition to chlorogenic acid, the study is the first to report the presence of sinapic, gallic, and m-hydroxybenzoic acids in the Amaryllidaceae. Chromatographic separation of S. puniceus led to the isolation of haemanthamine (1), haemanthidine (2), and a rare chlorinated amide, metolachlor (3), the natural occurrence of which is described for the first time. Haemanthamine, haemanthidine, and metolachlor displayed strong acetylcholinesterase inhibitory activity (IC50 ; 23.1, 23.7, and 11.5 μM, respectively). These results substantiate the frequent use of S. puniceus as a medicinal plant and hold much promise for further pharmaceutical development.
- MeSH
- acetamidy chemie izolace a purifikace metabolismus farmakologie MeSH
- alkaloidy amarylkovitých chemie izolace a purifikace metabolismus farmakologie MeSH
- Amaryllidaceae chemie metabolismus MeSH
- cholinesterasové inhibitory chemie izolace a purifikace farmakologie MeSH
- fenantridiny chemie izolace a purifikace metabolismus farmakologie MeSH
- kyseliny kumarové chemie izolace a purifikace metabolismus farmakologie MeSH
- léčivé rostliny chemie MeSH
- rostlinné extrakty chemie izolace a purifikace metabolismus farmakologie MeSH
- tandemová hmotnostní spektrometrie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Jihoafrická republika MeSH
Warfarin is a commonly used anticoagulant drug and is a derivate of coumarin. Cytochrome P450 2C9 (CYP2C9) plays the key role in transformation of coumarin and thus, influences determination of warfarin dosage. A number of factors including dietary compounds such as sesamin, caffeic acid and ferulic acids can regulate the activity of CYP2C9. The present study tested the hypothesis that sesamin, episesamin, caffeic acid and ferulic acid decreases the rate of warfarin 7-hydroxylation via inhibition of hepatic CYP2C9. The experiments were conducted on hepatic microsomes from human donors. It was demonstrated that the rate of 7-hydroxylation of warfarin was significantly decreased in the presence of sesamin in the range of concentrations from 5 to 500 nM, and was not affected by episesamin, caffeic acid and ferulic acid in the same range of concentrations. The kinetic analysis indicated non-competitive type of inhibition by sesamin with Ki = 202 ± 18 nM. In conclusion, the results of our in vitro study revealed that sesamin was able to inhibit formation of a major metabolite of warfarin, 7-hydroxywarfarin. The potentially negative consequences of the consumption of high amounts of sesamin-containing food or dietary supplements in warfarin-treated patients need to be further studied.
- MeSH
- antikoagulancia metabolismus MeSH
- dioxoly chemie farmakologie MeSH
- hydroxylace MeSH
- inhibiční koncentrace 50 MeSH
- jaterní mikrozomy metabolismus MeSH
- kinetika MeSH
- kyseliny kávové farmakologie MeSH
- kyseliny kumarové farmakologie MeSH
- lidé MeSH
- lignany chemie farmakologie MeSH
- potraviny MeSH
- potravní doplňky MeSH
- warfarin metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- antioxidancia chemická syntéza chemie farmakologie MeSH
- buněčná smrt účinky léků MeSH
- buňky Hep G2 MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- cholinesterasy metabolismus MeSH
- faktor 2 související s NF-E2 agonisté metabolismus MeSH
- kyseliny kumarové chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- melatonin chemická syntéza chemie farmakologie MeSH
- molekulární struktura MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
