A series of antioxidants was designed and synthesized based on conjugation of the hepatoprotective flavonolignan silybin with l-ascorbic acid, trolox alcohol or tyrosol via a C12 aliphatic linker. These hybrid molecules were prepared from 12-vinyl dodecanedioate-23-O-silybin using the enzymatic regioselective acylation procedure with Novozym 435 (lipase B) or with lipase PS. Voltammetric analyses showed that the silybin-ascorbic acid conjugate exhibited excellent electron donating ability, in comparison to the other conjugates. Free radical scavenging, antioxidant activities and cytoprotective action were evaluated. The silybin-ascorbic acid hybrid exhibited the best activities (IC50 = 30.2 μM) in terms of lipid peroxidation inhibition. The promising protective action of the conjugate against lipid peroxidation can be attributed to modulated electron transfer abilities of both the silybin and ascorbate moieties, but also to the hydrophobic C12 linker facilitating membrane insertion. This was supported experimentally and theoretically by density functional theory (DFT) and molecular dynamics (MD) calculations. The results presented here can be used in the further development of novel multipotent antioxidants and cytoprotective agents, in particular for substances acting at an aqueous/lipid interface.
- MeSH
- antioxidancia chemie metabolismus farmakologie MeSH
- buněčná membrána metabolismus MeSH
- buňky Hep G2 MeSH
- cytoprotekce účinky léků MeSH
- flavonolignany chemie metabolismus farmakologie MeSH
- játra cytologie účinky léků metabolismus MeSH
- lidé MeSH
- lipasa metabolismus MeSH
- molekulární konformace MeSH
- peroxidace lipidů účinky léků MeSH
- silymarin chemie MeSH
- simulace molekulární dynamiky MeSH
- transport elektronů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A series of isoquercitrin (quercetin-3-O-β-d-glucopyranoside) esters with mono- or dicarboxylic acids was designed to modulate hydro- and lipophilicity and biological properties. Esterification of isoquercitrin was accomplished by direct chemoenzymatic reaction using Novozym 435 (lipase from Candida antarctica), which accepted C₅- to C12-dicarboxylic acids; the shorter ones, such as oxalic (C₂), malonic (C₃), succinic (C₄) and maleic (C₄) acids were not substrates of the lipase. Lipophilicity of monocarboxylic acid derivatives, measured as log P, increased with the chain length. Esters with glutaric and adipic acids exhibited hydrophilicity, and the dodecanedioic acid hemiester was more lipophilic. All derivatives were less able to reduce Folin-Ciocalteau reagent (FCR) and scavenge DPPH (1,1-diphenyl-2-picrylhydrazyl) than isoquercitrin; ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) radical-scavenging activity was comparable. Dodecanoate and palmitate were the least active in FCR and ABTS scavenging; dodecanoate and hemiglutarate were the strongest DPPH scavengers. In contrast, most derivatives were much better inhibitors of microsomal lipoperoxidation than isoquercitrin; butyrate and hexanoate were the most efficient. Anti-lipoperoxidant activity of monocarboxylic derivatives, except acetates, decreased with increasing aliphatic chain. The opposite trend was noted for dicarboxylic acid hemiesters, isoquercitrin hemidodecanedioate being the most active. Overall, IQ butyrate, hexanoate and hemidodecanedioate are the most promising candidates for further studies.
- MeSH
- antioxidancia chemická syntéza chemie farmakologie MeSH
- estery chemická syntéza chemie farmakologie MeSH
- katalýza MeSH
- kyseliny dikarboxylové chemie MeSH
- kyseliny karboxylové chemie MeSH
- molekulární struktura MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- quercetin analogy a deriváty chemická syntéza chemie farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
A panel of lipases was screened for the selective acetylation and alcoholysis of silychristin and silychristin peracetate, respectively. Acetylation at primary alcoholic group (C-22) of silychristin was accomplished by lipase PS (Pseudomonas cepacia) immobilized on diatomite using vinyl acetate as an acetyl donor, whereas selective deacetylation of 22-O-acetyl silychristin was accomplished by Novozym 435 in methyl tert-butyl ether/ n-butanol. Both of these reactions occurred without diastereomeric discrimination of silychristin A and B. Both of these enzymes were found to be capable to regioselective deacetylation of hexaacetyl silychristin to afford penta-, tetra- and tri-acetyl derivatives, which could be obtained as pure synthons for further selective modifications of the parent molecule.
- MeSH
- acetáty chemická syntéza MeSH
- acetylace MeSH
- bakteriální proteiny metabolismus MeSH
- biokatalýza MeSH
- Burkholderia cepacia enzymologie MeSH
- enzymy imobilizované metabolismus MeSH
- lipasa metabolismus MeSH
- molekulární struktura MeSH
- registrace MeSH
- silymarin chemie MeSH
- stereoizomerie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Divalent or multivalent molecules often show enhanced biological activity relative to the simple monomeric units. Here we present enzymatically and chemically prepared dimers of the flavonolignans silybin and 2,3-dehydrosilybin. Their electrochemical behavior was studied by in situ and ex situ square wave voltammetry. The oxidation of monomers and dimers was similar, but adsorption onto the electrode and cell surfaces was different. A 1,1-diphenyl-2-picrylhydrazyl (DPPH) and an inhibition of microsomal lipoperoxidation assay were performed with same trend of results for silybin and 2,3-dehydrosilybin dimers. Silybin dimer showed better activity than the monomer, while on the contrary 2,3-dehydrosilybin dimer presented weaker antioxidant/antilipoperoxidant activity than its monomer. Cytotoxicity was evaluated on human umbilical vein endothelial cells, normal human adult keratinocytes, mouse fibroblasts (BALB/c 3T3) and human liver hepatocellular carcinoma cell line (HepG2). Silybin dimer was more cytotoxic than the parent compound and in the case of 2,3-dehydrosilybin its dimer showed weaker cytotoxicity than the monomer.
- MeSH
- bifenylové sloučeniny antagonisté a inhibitory MeSH
- biokatalýza MeSH
- buňky Hep G2 MeSH
- dimerizace MeSH
- endoteliální buňky pupečníkové žíly (lidské) MeSH
- fibroblasty cytologie účinky léků MeSH
- fungální proteiny chemie MeSH
- jaterní mikrozomy účinky léků MeSH
- keratinocyty cytologie účinky léků MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lipasa chemie MeSH
- myši MeSH
- oxidace-redukce MeSH
- peroxidace lipidů účinky léků MeSH
- pikráty antagonisté a inhibitory MeSH
- scavengery volných radikálů chemická syntéza farmakologie MeSH
- silymarin chemická syntéza farmakologie MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of new isoniazid hydrazones was synthesized by two procedures. In the first isoniazid was activated with diethoxymethyl acetate and condensed with the appropriate anilines. Alternatively, substituted anilines were activated by diethoxymethyl acetate and subsequently condensed with isoniazid. NMR study confirmed that both synthetic approaches gave the same tautomer. All compounds were screened for in vitro antimycobacterial activity. Most of them exhibited the same activity against Mycobacterium tuberculosis (MIC 1 μmol L(-1)) as isoniazid (INH), better activity against Mycobacterium kansasii 325/80 (MIC 0.125-0.250 μmol L(-1)), high value of selectivity index (SI) and IC(50) between 0.0218 and 0.326 mmol L(-1). Compound 2o with the best SI was used as a model compound for the stability test and was found to be stable at neutral pH, but under acidic conditions it slowly hydrolysed.
- MeSH
- antibakteriální látky chemie farmakologie MeSH
- antituberkulotika chemie farmakologie MeSH
- atypické mykobakteriální infekce farmakoterapie MeSH
- buňky Hep G2 MeSH
- hydrazony chemie farmakologie MeSH
- intracelulární infekce bakterií Mycobacterium avium farmakoterapie MeSH
- isoniazid chemie farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium avium komplex účinky léků MeSH
- Mycobacterium kansasii účinky léků MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- tuberkulóza farmakoterapie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chitosan is a linear polysaccharide with a good biodegradability, biocompatibility, and no toxicity, which provide it with huge potential for future development. The chitosan molecule appears to be a suitable polymeric complex for many biomedical applications. This review gathers current findings on the antibacterial, antifungal, antitumour and antioxidant activities of chitosan derivatives and concurs with our previous review presenting data collected up to 2008. Antibacterial activity is based on molecular weight, the degree of deacetylation, the type of substitutents, which can be cationic or easily form cations, and the type of bacterium. In general, high molecular weight chitosan cannot pass through cell membranes and forms a film that protects cells against nutrient transport through the microbial cell membrane. Low molecular weight chitosan derivatives are water soluble and can better incorporate the active molecule into the cell. Gram-negative bacteria, often represented by Escherichia coli, have an anionic bacterial surface on which cationic chitosan derivatives interact electrostatically. Thus, many chitosan conjugates have cationic components such as ammonium, pyridinium or piperazinium substituents introduced into their molecules to increase their positive charge. Gram-positive bacteria like Staphylococcus aureus are inhibited by the binding of lower molecular weight chitosan derivatives to DNA or RNA. Chitosan nanoparticles exhibit an increase in loading capacity and efficacy. Antitumour active compounds such as doxorubicin, paclitaxel, docetaxel and norcantharidin are used as drug carriers. It is evident that chitosan, with its low molecular weight, is a useful carrier for molecular drugs requiring targeted delivery. The antioxidant scavenging activity of chitosan has been established by the strong hydrogen-donating ability of chitosan. The low molecular weight and greater degree of quarternization have a positive influence on the antioxidant activity of chitosan. Phenolic and polyphenolic compounds with antioxidant effects are condensed with chitosan to form mutual prodrugs.
- MeSH
- antiinfekční látky chemie farmakologie terapeutické užití MeSH
- antioxidancia chemie farmakologie terapeutické užití MeSH
- antitumorózní látky chemie farmakologie terapeutické užití MeSH
- chitosan analogy a deriváty chemie farmakologie terapeutické užití MeSH
- lidé MeSH
- molekulární struktura MeSH
- racionální návrh léčiv MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Several new fluorine-containing hydrazones were synthesized and screened for their in vitro antimycobacterial activity. Nine of these derivatives have shown a remarkable activity against MDR-TB strain with MIC 0.5 μg/mL and high value of selectivity index (SI). Compound 3h with the highest SI (1268.58) was used for stability evaluation with putative metabolites (ciprofloxacin and formylciprofloxacin) detection. Compound 3h was stable at pH 7.4 of aqueous buffer and rat plasma, in acidic buffers (at pH 3 and 5) slow decomposition was observed. Interestingly, no formylciprofloxacin was detected in the solution, and only slightly increased concentration of ciprofloxacin was observed instead. Trifluoromethyl hydrazones 3f and 3g exhibited the best activity also against two strains of Mycobacterium kansasii (MIC 1-4 μmol/L). All evaluated compounds were found to be non-cytotoxic.
- MeSH
- antituberkulotika chemie metabolismus farmakologie MeSH
- buněčné linie MeSH
- fluor chemie metabolismus farmakologie MeSH
- hydrazony chemie metabolismus farmakologie MeSH
- krevní plazma metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- multirezistentní tuberkulóza farmakoterapie MeSH
- Mycobacterium kansasii účinky léků MeSH
- Mycobacterium účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of 27 salicylanilide-based carbamates was prepared as a part of our ongoing search for new antituberculosis drugs. These compounds exhibited very good in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium and, in particular, against five multidrug-resistant strains, with MIC values between 0.5-2 micromol/L. Moreover, they displayed moderate toxicity against intestinal cells with the selectivity index being up to 96. Furthermore, acid stability and a half-life of 43h at pH 7.4 were shown. Thus, these novel salicylanilide derivatives are drug candidates which should be seriously consider for further screening.
- MeSH
- antituberkulotika chemie farmakologie MeSH
- buněčné linie MeSH
- karbamáty chemie farmakologie MeSH
- lidé MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- proliferace buněk účinky léků MeSH
- salicylanilidy chemie farmakologie MeSH
- tuberkulóza farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chitosan is a prospective cationic polysaccharide which shows a number of functions in many fields, including biomedicinal, pharmaceutical, preservation, microbial and others. In this review, we have summarized three main areas of its biomedicinal applications due to its antimicrobial, anticancer, and antioxidant effects. The applications are influenced by a number of factors such as its polymerization degree, the degree of chitin deacetylation and some other physicochemical properties. The biodegradable, nontoxic and non-allergenic nature of chitosan suggests its use as a carrier in drug delivery systems.
- MeSH
- antibakteriální látky farmakologie chemie terapeutické užití MeSH
- antifungální látky farmakologie chemie terapeutické užití MeSH
- antioxidancia farmakologie chemie terapeutické užití MeSH
- antitumorózní látky farmakologie chemie terapeutické užití MeSH
- chitosan farmakologie klasifikace terapeutické užití MeSH
- farmaceutický průmysl metody trendy MeSH
- financování organizované MeSH
- lidé MeSH
- nosiče léků terapeutické užití MeSH
- polymery terapeutické užití MeSH
- systémy cílené aplikace léků metody využití MeSH
- Check Tag
- lidé MeSH
