Juglone Dotaz Zobrazit nápovědu
A series of 11-substituted 9-hydroxy-3,5,10,11-tetrahydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]thiazole-2,5,10-triones 3.1-3.13 were synthesized via hetero-Diels-Alder reaction of 5-ene-4-thioxo-2-thiazolidinones and 5-hydroxy-1,4-naphthoquinone (juglone). The structure of newly synthesized compounds was established by means of spectral data and a single-crystal X-ray diffraction analysis. The synthesized compounds were tested on a panel of cell lines representing different types of cancer as well as normal and pseudonormal cells and peripheral human blood lymphocytes. Compound 3.10 was found to be the most active derivative, exhibiting a cytotoxic effect similar to doxorubicin's one (IC50 ranged from 0.6 to 5.98 μM), but less toxic to normal and pseudonormal cells. All synthesized compounds were able to interact with DNA, although their anticancer activity did not correlate with the potency of interaction with DNA. The status of p53 in colorectal cancer cells correlated with the activity of the synthesized derivatives 3.1, 3.7, and 3.10. Compound 3.10 did not have an acute toxic effect on the body of С57BL/6 mice, unlike the well-known anticancer drug doxorubicin, which was used as a positive control. The injection of 3.10 (20 mg/kg) to mice had no effect on the counts of leukocytes, erythrocytes, platelets and hemoglobin level in their blood, in contrast to doxorubicin, which caused anemia and leukopenia, indicating bio-tolerance of 3.10in vivo.
- MeSH
- doxorubicin farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- naftochinony * farmakologie MeSH
- proliferace buněk MeSH
- protinádorové látky * chemie MeSH
- screeningové testy protinádorových léčiv MeSH
- simulace molekulového dockingu MeSH
- thiazoly chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Naftochinony představují v přírodě poměrně rozšířené látky fenolického charakteru. Jedná se o produkty bakteriálního, fungálního, stejně jako sekundárního metabolizmu vyšších rostlin. Mezi nejrozšířenější patří juglon, lawson a plumbagin. Naftochinony jsou díky širokým farmakologickým účinkům velmi zajímavé látky. Vykazují vysokou cytotoxicitu, rovněž vlastnosti antibakteriální, antifungální, antivirální, antiparazitální, insekticidní, antiflogistické a antipyretické. Dokázány byly také významné farmakologické účinky na kardiovaskulární a reprodukční systém. Mechanizmus jejich účinku je velmi široký a komplexní – vážou se k DNA a inhibují procesy replikace, interagují s četnými proteiny (enzymy), a poškozují tak integritu buněčných i mitochondriálních membrán, zasahují do přenosu elektronů na mitochondriálních membránách. Rostliny s obsahem naftochinonů našly využití i v tradičních léčitelstvích některých národů – jsou po dlouhá staletí využívány především v Číně a ve státech Jižní Ameriky, kde nacházejí uplatnění zejména v léčbě nádorových a parazitárních onemocnění.
Naphthoquinones are wide-spread phenolic compounds in nature. They are products of bacterial and fungal as well as high-plants secondary metabolism. Juglone, lawsone, and plumbagin are the most widespread compounds. Naphthoquinones display very significant pharmacological properties – they are cytotoxic, they have significant antibacterial, antifungal, antiviral, insecticidal, antiinflammatory, and antipyretic properties. Pharmacological effects to cardiovascular and reproductive systems have been demonstrated too. The mechanism of their effect is highly large and complex – they bind to DNA and inhibit the processes of replication, interact with numerous proteins (enzymes) and disturb cell and mitochondrial membranes, interfere with electrons of the respiratory chain on mitochondrial membranes. Plants with naphthoquinone content are widely used in China and the countries of South America, where they are applied to malignant and parasitic diseases treatment.
In this study, ten anthra-, nine naphtho-, and five benzoquinone compounds of natural origin and five synthetic naphthoquinones were assessed, using an enzymatic in vitro assay, for their potential to inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2), the key enzymes of the arachidonic acid cascade. IC₅₀ values comparable with COX reference inhibitor indomethacin were recorded for several quinones (primin, alkannin, diospyrin, juglone, 7-methyljuglone, and shikonin). For some of the compounds, we suggest the redox potential of quinones as the mechanism responsible for in vitro COX inhibition because of the quantitative correlation with their pro-oxidant effect. Structure-relationship activity studies revealed that the substitutions at positions 2 and 5 play the key roles in the COX inhibitory and pro-oxidant actions of naphthoquinones. In contrast, the redox mechanism alone could not explain the activity of primin, embelin, alkannin, and diospyrin. For these four quinones, molecular modeling suggested similar binding modes as for conventional nonsteroidal anti-inflammatory drugs (NSAIDs).
- MeSH
- antiflogistika farmakologie MeSH
- chinony chemie farmakologie MeSH
- cyklooxygenasa 1 chemie metabolismus MeSH
- cyklooxygenasa 2 chemie metabolismus MeSH
- inhibitory cyklooxygenasy chemie farmakologie MeSH
- lidé MeSH
- molekulární modely MeSH
- myši MeSH
- ovce MeSH
- oxidace-redukce MeSH
- rostlinné extrakty farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A small library of 2-[(1H-indol-3-yl)methyl]-5-(alkylthio)-1,3,4-oxadiazoles was prepared, starting from indole-3-acetic acid methyl ester and its 5-methyl-substituted derivative. The synthetic route involved the formation of intermediate hydrazides, their condensation with carbon disulfide, and intramolecular cyclization to corresponding 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones. The latter were then S-alkylated, and in case of ester derivatives, they were further hydrolyzed into corresponding carboxylic acids. All 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones and their S-alkylated derivatives were then screened for their protective effects in vitro and in vivo. Methyl substitution on the indole ring and propyl, butyl, or benzyl substitution on sulfhydryl group-possessing compounds were revealed to protect Friedreich's ataxia fibroblasts against the effects of glutathione depletion induced by the γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine. Two of the active compounds also reproducibly increased the survival of Caenorhabditis elegans exposed to juglone-induced oxidative stress.
- MeSH
- acetáty chemická syntéza MeSH
- antioxidancia * chemická syntéza chemie farmakologie MeSH
- Caenorhabditis elegans MeSH
- Friedreichova ataxie farmakoterapie metabolismus patologie MeSH
- indoly * chemie farmakologie MeSH
- kultivované buňky MeSH
- kyseliny indoloctové chemie MeSH
- lidé MeSH
- oxadiazoly * chemická syntéza chemie farmakologie MeSH
- oxidační stres účinky léků MeSH
- thioketony * chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Naphthoquinones represent the group of plant secondary metabolites with cytotoxic properties based on their ability to generate reactive oxygen species and interfere with the processes of cell respiration. Due to this fact, the possible cytotoxic mechanisms on cellular and subcellular levels are investigated intensively. There are many targets of cytotoxic action on the cellular level; however, DNA is a critical target of many cytotoxic compounds. Due to the cytotoxic properties of naphthoquinones, it is necessary to study the processes of naphthoquinones, DNA interactions (1,4-naphthoquinone, binapthoquinone, juglone, lawsone, plumbagin), especially by using modern analytical techniques. In our work, the Raman spectroscopy was used to determine the possible binding sites of the naphthoquinones on the DNA and to characterize the bond of naphthoquinone to DNA. Experimental data reveals the relationships between the perturbations of structure-sensitive Raman bands and the types of the naphthoquinones involved. The modification of DNA by the studied naphthoquinones leads to the nonspecific interaction, which causes the transition of B-DNA into A-DNA conformation. The change of the B-conformation of DNA for all measured DNA modified by naphthoquinones except plumbagin is obvious.
- MeSH
- B-DNA chemie metabolismus MeSH
- DNA chemie metabolismus MeSH
- naftochinony chemie metabolismus MeSH
- Ramanova spektroskopie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- rostliny chemie metabolismus MeSH
- sekundární metabolismus * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Over the past decades, a number of 1,4-naphthoquinones have been isolated from natural resources and several of naphthoquinone derivatives with diverse structural motif have been synthesized; they possess a multitude of biochemical properties and modulate numerous pharmacological roles that offer new targets for addressing the challenges pertaining to novel drug developments. Among natural naphthoquinones, lapachol, α-lapachone, β-lapachone, lawsone, juglone, and plumbagin have been evaluated for its potential as antitrypanosomal activities. The chemotherapeutic drugs available for combating human trypanosomiasis, that is, American trypanosomiasis and African trypanosomiasis caused by Trypanosoma cruzi and Trypanosoma brucei, respectively, and animal tripanosomosis caused by Trypanosoma evansi have a problem of drug resistance and several toxic effect. Therefore, search of alternative effective drug molecules, without toxic effects, have enthused the researchers for searching new drug entity with potential clinical efficacy. In the search for new antitrypanosomal compound, this review focuses on different natural quinones and their synthetic derivatives associated with antitrypanosomal studies. In this context, this review will be useful for the development of new antitrypanosomal drugs mainly based on different structural modification of natural and synthetic naphthoquinones.
- MeSH
- Chagasova nemoc * farmakoterapie MeSH
- lidé MeSH
- naftochinony * chemie MeSH
- paraziti * MeSH
- Trypanosoma cruzi * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Eleven 6-furfurylaminopurine (kinetin, Kin) derivatives were synthesized to obtain biologically active compounds. The prepared compounds were characterized using 1H NMR, mass spectrometry combined with HPLC purity determination and elemental C, H, N analyses. The biological activity of new derivatives was tested on plant cells and tissues in cytokinin bioassays, such as tobacco callus, detached wheat leaf chlorophyll retention bioassay and Amaranthus bioassay. The selected compounds were subsequently tested on normal human dermal fibroblasts (NHDF) and keratinocyte cell lines (HaCaT) to exclude possible phototoxic effects and, on the other hand, to reveal possible UVA and UVB photoprotective activity. The protective antioxidant activity of the prepared cytokinin derivatives was further studied and compared to previously prepared antisenescent compound 6-furfurylamino-9-(tetrahydrofuran-2-yl)purine (Kin-THF) using induced oxidative stress (OS) on nematode Caenorhabditis elegans damaged by 5-hydroxy-1,4-naphthoquinone (juglone), a generator of reactive oxygen species. The observed biological activity was interpreted in relation to the structure of the prepared derivatives. The most potent oxidative stress protection of all the prepared compounds was shown by 6-(thiophen-2-ylmethylamino)-9-(tetrahydrofuran-2-yl)purine (6) and 2-chloro-6-furfurylamino-9-(tetrahydrofuran-2-yl)purine (9) derivatives and the results were comparable to Kin-THF. Compounds 6 and 9 were able to significantly protect human skin cells against UV radiation in vitro. Both the derivatives 6 and 9 showed higher protective activity in comparison to previously known structurally similar compounds Kin and Kin-THF. The obtained results are surprising due to the fact that the prepared compounds showed to be inactive in the ORAC assay which proved that the compounds did not act as direct antioxidants as they were unable to directly scavenge oxygen radicals.
- MeSH
- cytokininy chemická syntéza chemie farmakologie MeSH
- kůže účinky léků MeSH
- lidé MeSH
- molekulární struktura MeSH
- ochranné látky chemická syntéza chemie farmakologie MeSH
- oxidační stres účinky léků MeSH
- ultrafialové záření * MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
