Multidrug resistance (MDR) is a major challenge for the 21th century in both cancer chemotherapy and antibiotic treatment of bacterial infections. Efflux pumps and transport proteins play an important role in MDR. Compounds displaying inhibitory activity toward these proteins are prospective for adjuvant treatment of such conditions. Natural low-cost and nontoxic flavonoids, thanks to their vast structural diversity, offer a great pool of lead structures with broad possibility of chemical derivatizations. Various flavonoids were found to reverse both antineoplastic and bacterial multidrug resistance by inhibiting Adenosine triphosphate Binding Cassette (ABC)-transporters (human P-glycoprotein, multidrug resistance-associated protein MRP-1, breast cancer resistance protein, and bacterial ABC transporters), as well as other bacterial drug efflux pumps: major facilitator superfamily (MFS), multidrug and toxic compound extrusion (MATE), small multidrug resistance (SMR) and resistance-nodulation-cell-division (RND) transporters, and glucose transporters. Flavonoids and particularly flavonolignans are therefore highly prospective compounds for defying multidrug resistance.
- MeSH
- ABC transportéry antagonisté a inhibitory genetika metabolismus MeSH
- antibakteriální látky farmakologie MeSH
- antitumorózní látky terapeutické užití MeSH
- Bacteria genetika metabolismus MeSH
- bakteriální infekce farmakoterapie mikrobiologie MeSH
- bakteriální léková rezistence * MeSH
- bakteriální proteiny antagonisté a inhibitory genetika metabolismus MeSH
- chemorezistence * MeSH
- flavonoidy aplikace a dávkování MeSH
- flavonolignany aplikace a dávkování MeSH
- lidé MeSH
- nádory farmakoterapie genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Silychristin A is the second most abundant compound of silymarin. Silymarin complex was previously described as an antioxidant with multidrug resistance modulation activity. Here, the results of a classical biochemical antioxidant assay (ORAC) were compared with a cellular assay evaluating the antioxidant capacity of pure silychristin A and its derivatives (anhydrosilychristin, isosilychristin and 2,3-dehydrosilychristin A). All the tested compounds acted as antioxidants within the cells, but 2,3-dehydro- and anhydro derivatives were almost twice as potent as the other tested compounds. Similar results were obtained in LPS-stimulated macrophages, where 2,3-dehydro- and anhydrosilychristin inhibited NO production nearly twice as efficiently as silychristin A. The inhibition of P-glycoprotein (P-gp) was determined in vitro, and the respective sensitization of doxorubicin-resistant ovarian carcinoma overproducing P-gp was detected. Despite the fact that the inhibition of P-gp was demonstrated in a concentration-dependent manner for each tested compound, the sensitization of the resistant cell line was observed predominantly for silychristin A and 2,3-dehydrosilychristin A. However, anhydrosilychristin and isosilychristin affected the expression of both the P-gp (ABCB1) and ABCG2 genes. This is the first report showing that silychristin A and its 2,3-dehydro-derivative modulate multidrug resistance by the direct inhibition of P-gp, in contrast to anhydrosilychristin and isosilychristin modulating multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps.
- Publikační typ
- časopisecké články MeSH
Isoquercitrin, (IQ, quercetin-3-O-β-d-glucopyranoside) is known for strong chemoprotectant activities. Acylation of flavonoid glucosides with carboxylic acids containing an aromatic ring brings entirely new properties to these compounds. Here, we describe the chemical and enzymatic synthesis of a series of IQ derivatives at the C-6″. IQ benzoate, phenylacetate, phenylpropanoate and cinnamate were prepared from respective vinyl esters using Novozym 435 (Lipase B fromCandida antarcticaimmobilized on acrylic resin). The enzymatic procedure gave no products with "hydroxyaromatic" acids, their vinyl esters nor with their benzyl-protected forms. A chemical protection/deprotection method using Steglich reaction yielded IQ 4-hydroxybenzoate, vanillate and gallate. In case ofp-coumaric, caffeic, and ferulic acid, the deprotection lead to the saturation of the double bonds at the phenylpropanoic moiety and yielded 4-hydroxy-, 3,4-dihydroxy- and 3-methoxy-4-hydroxy-phenylpropanoates. Reducing capacity of the cinnamate, gallate and 4-hydroxyphenylpropanoate towards Folin-Ciocalteau reagent was significantly lower than that of IQ, while other derivatives displayed slightly better or comparable capacity. Compared to isoquercitrin, most derivatives were less active in 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, but they showed significantly better 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid, ABTS) scavenging activity and were substantially more active in the inhibition oftert-butylhydroperoxide induced lipid peroxidation of rat liver microsomes. The most active compounds were the hydroxyphenylpropanoates.
- MeSH
- estery * chemie MeSH
- hmotnostní spektrometrie MeSH
- molekulární struktura MeSH
- nukleární magnetická rezonance biomolekulární MeSH
- peroxidace lipidů účinky léků MeSH
- quercetin analogy a deriváty analýza chemická syntéza farmakologie MeSH
- scavengery volných radikálů analýza chemická syntéza farmakologie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Publikační typ
- časopisecké články MeSH
Flavonolignans are plant natural products, composed of a flavonoid moiety and a lignan (phenylpropanoid) part. Current literature focuses on flavonolignans formed from taxifolin and coniferyl alcohol as e.g. silybin and its congeners from fruit extract from the purple variety of the milk thistle (Silybum marianum) denoted as "silymarin". This review describes chemistry and biological activity of so far neglected "non-taxifolin" based flavonolignans, derived from apigenin, luteolin, tricin, chrysoeriol, naringenin and eriodictyol, as the flavonoid part. Up-to-date knowledge on hydnocarpin, hydnocarpin-D, pseudotsuganol, hydnowightin, neohydnocarpin, palstatin, salcolins A and B, anastatins A and B, sinaiticin, silyamandin and silandrin is summarized in the present paper. Most of non-taxifolin derived flavonolignans have been shown to exhibit in vitro and/or in vivo anti-hepatotoxic, anti-oxidant, free radical scavenging, anti-inflammatory, anti-proliferative, anti-cancer, chemotherapy potentiating, anti-melanogenic, anti-bacterial, vasorelaxing, anti-platelet aggregation and/or hypotriglyceridemic activity, often stronger than silybin. Many of these compounds inhibited Staphylococcus aureus multidrug resistance pump NorA and sensitized multidrug resistant cancer cell lines showing a potential as adjuvants. Non-taxifolin derived flavonolignans are a relatively unexplored group of compounds with interesting biological activity and great application potential. Their detailed study could provide a new insight into the biomimetic synthesis in order to obtain new compounds with greater activity and identify new lead structures for the biomedicinal research.
- MeSH
- antiflogistika chemie izolace a purifikace farmakologie MeSH
- antioxidancia chemie izolace a purifikace farmakologie MeSH
- antitumorózní látky chemie izolace a purifikace farmakologie MeSH
- flavonolignany chemie izolace a purifikace farmakologie MeSH
- fytonutrienty chemie izolace a purifikace farmakologie MeSH
- lidé MeSH
- ostropestřec mariánský MeSH
- quercetin analogy a deriváty chemie izolace a purifikace farmakologie MeSH
- rostlinné extrakty chemie izolace a purifikace farmakologie MeSH
- Staphylococcus aureus účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
