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
- Názvy látek
- 4-coumaric acid methyl ester MeSH Prohlížeč
- antitumorózní látky MeSH
- cyklohexanony MeSH
- hydroxylový radikál MeSH
- kyseliny kumarové MeSH
- scavengery volných radikálů 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.
- Klíčová slova
- Amaryllidaceae, NMR, alkaloids, chromatography, paintbrush lily, phenolics,
- 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
- Názvy látek
- acetamidy MeSH
- alkaloidy amarylkovitých MeSH
- cholinesterasové inhibitory MeSH
- fenantridiny MeSH
- hemanthamine MeSH Prohlížeč
- hemanthidine MeSH Prohlížeč
- kyseliny kumarové MeSH
- metolachlor MeSH Prohlížeč
- rostlinné extrakty 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.
- Klíčová slova
- Cytochrome P450, Detoxification, Food-drug interactions, In vitro, S-7-hydroxywarfarin,
- 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
- Názvy látek
- antikoagulancia MeSH
- caffeic acid MeSH Prohlížeč
- dioxoly MeSH
- ferulic acid MeSH Prohlížeč
- kyseliny kávové MeSH
- kyseliny kumarové MeSH
- lignany MeSH
- sesamin MeSH Prohlížeč
- warfarin 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
- práce podpořená grantem MeSH
- Názvy látek
- antioxidancia MeSH
- cholinesterasové inhibitory MeSH
- cholinesterasy MeSH
- faktor 2 související s NF-E2 MeSH
- ferulic acid MeSH Prohlížeč
- kyseliny kumarové MeSH
- melatonin MeSH
Micropropagation of Hypoxis hemerocallidea Fisch. and C.A. Mey was used as a model system to study the influence of cytokinins (CKs) on plant regeneration and biochemical accumulation of hydroxybenzoic and hydroxycinnamic acid derivatives in organ and callus cultures and their antioxidant activity. Fourteen free phenolic acids were detected using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) while antioxidant activity was evaluated using oxygen radical absorbance capacity (ORAC) and 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging activity. Cytokinins had a significant effect on the biochemical accumulation of hydroxybenzoic and hydroxycinnamic acid derivatives in H. hemerocallidea organ cultures. In particular, meta-topolin-treated organ cultures produced high concentrations of gallic, protocatechuic, gentisic, p-hydroxybenzoic, m-hydroxybenzoic, salicylic, chlorogenic and trans-cinnamic acids. The isoprenoid CK, N(6)-(2-isopentenyl)-adenine significantly increased the accumulation of hydroxycinnamic acid derivatives, namely, caffeic, p-coumaric, sinapic and ferulic acids. Cytokinin-treated organ cultures exhibited a significant increase in antioxidant activity, particularly in the ORAC model. In callus cultures, CKs decreased the concentrations of hydroxycinnamic acid derivatives and antioxidant activity when compared to the control. Overall, both CK type and concentration had a significant effect on plant regeneration, callus proliferation, biochemical accumulation of free phenolic acids and antioxidant activity of the resultant extracts.
- Klíčová slova
- Antioxidants, Hydroxybenzoic acids, Hydroxycinnamic acids, Hypoxidaceae, Organogenesis, Secondary metabolites,
- MeSH
- antioxidancia metabolismus farmakologie MeSH
- bifenylové sloučeniny metabolismus MeSH
- cytokininy farmakologie MeSH
- fenoly metabolismus farmakologie MeSH
- hydroxybenzoáty metabolismus farmakologie MeSH
- Hypoxis růst a vývoj metabolismus MeSH
- isopentenyladenosin farmakologie MeSH
- kyseliny kumarové metabolismus farmakologie MeSH
- pikráty metabolismus MeSH
- regenerace MeSH
- regulátory růstu rostlin farmakologie MeSH
- somatická embryogeneze rostlin MeSH
- stavba rostlin růst a vývoj metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 1,1-diphenyl-2-picrylhydrazyl MeSH Prohlížeč
- antioxidancia MeSH
- bifenylové sloučeniny MeSH
- cytokininy MeSH
- fenoly MeSH
- hydroxybenzoáty MeSH
- isopentenyladenosin MeSH
- kyseliny kumarové MeSH
- N(6)-(delta(2)-isopentenyl)adenine MeSH Prohlížeč
- pikráty MeSH
- regulátory růstu rostlin MeSH
Naturally occurring plant phenolics, p-coumaric acid (PA), caffeic acid (CA), ferulic acid (FA) and gentisic acid (GA) (25-100 nmol/L) had protective effects on acridine orange (AO; 216 mumol/L)- and ofloxacin (3 mumol/L)-induced genotoxicity in Salmonella typhimurium. FA, GA and CA exhibited a significant concentration-dependent protective effect against the genotoxicity of AO and ofloxacin, with the exception of PA, which at all concentrations tested abolished the AO and ofloxacin genotoxicity. UV spectrophotometric measurements showed the interaction of PA, FA, GA and CA with AO but not with ofloxacin; this interaction is obviously responsible for the reduction of AO-induced S. typhimurium mutagenicity. In the case of ofloxacin the antimutagenic effect of PA, FA, GA and CA is assumed to be a result of their ability to scavenge reactive oxygen species (ROS) produced by ofloxacin.
- MeSH
- akridinová oranž toxicita MeSH
- antimutagenní látky farmakologie MeSH
- gentisáty * MeSH
- hydroxybenzoáty farmakologie MeSH
- kyseliny kávové farmakologie MeSH
- kyseliny kumarové farmakologie MeSH
- mutageny toxicita MeSH
- ofloxacin toxicita MeSH
- propionáty MeSH
- Salmonella typhimurium účinky léků genetika MeSH
- testy genotoxicity MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 2,5-dihydroxybenzoic acid MeSH Prohlížeč
- akridinová oranž MeSH
- antimutagenní látky MeSH
- caffeic acid MeSH Prohlížeč
- ferulic acid MeSH Prohlížeč
- gentisáty * MeSH
- hydroxybenzoáty MeSH
- kyseliny kávové MeSH
- kyseliny kumarové MeSH
- mutageny MeSH
- ofloxacin MeSH
- p-coumaric acid MeSH Prohlížeč
- phenolic acid MeSH Prohlížeč
- propionáty MeSH
The physiological role of monocarboxylate transport in brown adipose tissue mitochondria has been reevaluated. We studied pyruvate, alpha-ketoisovalerate, alpha-ketoisocaproate, and phenylpyruvate uniport via the uncoupling protein (UCP1) as a GDP-sensitive swelling in K+ salts induced by valinomycin or by monensin and carbonyl cyanide-p-(trifluoromethoxy)phenylhydrazone in Na+ salts. We have demonstrated that this uniport is inhibited by fatty acids. GDP inhibition in K+ salts was not abolished by an uncoupler, indicating a negligible monocarboxylic acid penetration via the lipid bilayer. In contrast, the electroneutral pyruvate uptake (swelling in ammonium pyruvate or potassium pyruvate induced by change in pH) mediated by the pyruvate carrier was inhibited by its specific inhibitor alpha-cyano-4-hydroxycinnamate but not by fatty acids. Moreover, alpha-cyano-4-hydroxycinnamate enhanced the energization of brown adipose tissue mitochondria, which was monitored fluorometrically by 2-(4-dimethylaminostyryl)-1-methylpyridinium iodide and safranin O. Consequently, we suggest that UCP1 might participate in futile cycling of unipolar ketocarboxylates under certain physiological conditions while expelling these anions from the matrix. The cycle is completed on their return via the pyruvate carrier in an H+ symport mode.
- MeSH
- biologický transport MeSH
- guanosindifosfát farmakologie MeSH
- hnědá tuková tkáň metabolismus MeSH
- iontové kanály MeSH
- karbonylkyanid-p-trifluormethoxyfenylhydrazon farmakologie MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- křečci praví MeSH
- křeček rodu Mesocricetus MeSH
- kyseliny fenylpyrohroznové farmakologie MeSH
- kyseliny karboxylové metabolismus MeSH
- kyseliny kumarové farmakologie MeSH
- lipidové dvojvrstvy MeSH
- membránové proteiny metabolismus MeSH
- mitochondriální proteiny MeSH
- mitochondrie účinky léků metabolismus MeSH
- monensin farmakologie MeSH
- pyruváty metabolismus MeSH
- rotenon farmakologie MeSH
- transportní proteiny metabolismus MeSH
- uncoupling protein 1 MeSH
- valinomycin farmakologie MeSH
- zduření mitochondrií účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alpha-cyano-4-hydroxycinnamate MeSH Prohlížeč
- guanosindifosfát MeSH
- iontové kanály MeSH
- karbonylkyanid-p-trifluormethoxyfenylhydrazon MeSH
- kyseliny fenylpyrohroznové MeSH
- kyseliny karboxylové MeSH
- kyseliny kumarové MeSH
- lipidové dvojvrstvy MeSH
- membránové proteiny MeSH
- mitochondriální proteiny MeSH
- monensin MeSH
- phenylpyruvic acid MeSH Prohlížeč
- pyruváty MeSH
- rotenon MeSH
- transportní proteiny MeSH
- uncoupling protein 1 MeSH
- valinomycin MeSH
