Microtubule dynamic is exceptionally sensitive to modulation by small-molecule ligands. Our previous work presented the preparation of microtubule-targeting estradiol dimer (ED) with anticancer activity. In the present study, we explore the effect of selected linkers on the biological activity of the dimer. The linkers were designed as five-atom chains with carbon, nitrogen or oxygen in their centre. In addition, the central nitrogen was modified by a benzyl group with hydroxy or methoxy substituents and one derivative possessed an extended linker length. Thirteen new dimers were subjected to cytotoxicity assay and cell cycle profiling. Dimers containing linker with benzyl moiety substituted with one or more methoxy groups and longer branched ones were found inactive, whereas other structures had comparable efficacy as the original ED (e.g. D1 with IC50 = 1.53 μM). Cell cycle analysis and immunofluorescence proved the interference of dimers with microtubule assembly and mitosis. The proposed in silico model and calculated binding free energy by the MM-PBSA method were closely correlated with in vitro tubulin assembly assay.
- MeSH
- apoptóza MeSH
- ethinylestradiol * chemie farmakologie MeSH
- kontrolní body fáze G2 buněčného cyklu účinky léků MeSH
- mikrotubuly MeSH
- modulátory tubulinu * chemie farmakologie MeSH
- nádorové buněčné linie MeSH
- protinádorové látky * chemie farmakologie MeSH
- triazoly * chemie farmakologie MeSH
- tubulin * metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Testosterone derivatives and related compounds (such as anabolic-androgenic steroids-AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.
- MeSH
- lidé MeSH
- nové syntetické drogy chemie terapeutické užití MeSH
- prekurzory léčiv chemie terapeutické užití MeSH
- rostliny chemie MeSH
- steroidy chemie terapeutické užití MeSH
- testosteron agonisté analogy a deriváty chemie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Two valuable forensic tools based on enzyme-linked immunoassays (ELISAs) for the analysis of 17α-methylated steroids were developed using haptens of stanazolol and its conjugates with biotin. Haptens containing terminal carboxylic group were conjugated to bovine serum albumin (BSA), rabbit serum albumin (RSA) or ovalbumin (OVA). Eight batches of antisera (RAbs) obtained by immunization of rabbits were tested in an indirect competitive ELISA system using immobilization of RSA conjugate (RSA/hapten) and competitor immobilization of the biotinylated conjugate (AB-ELISA) to avidin (avidin/hapten). The best results were achieved with the RAb 212 antibodies in RSA/ST-3 and avidin/ST-10 assembled variants. For the RSA/ST-3 system, an IC50 of 0.3 ng/mL and a detection limit of 0.02 ng/mL were measured. In case of avidin/ST-10 variant, IC50 was of 3.9 ng/mL and a detection limit of 0.57 ng/mL were obtained. The effect of solvent was tested as well as the stability of coated microtiter plates over four-month period. The cross-reactivity of the developed assays with other anabolic steroids was tested and high sensitivity towards 17α-methylated steroids was observed. RSA/ST-3 assay showed significant cross-reactivity with 17α-methyltestosterone (81.2%), oxymetholone (30.4%), methandienone (10.0%) and methyl dihydrotestosterone (7.7%). Similarly, in the avidin/ST-10 assay, 17α-methyltestosterone (34.5%), mestanolone (32.1%), oxymetholone (22.7%), methandienone (14.2%), 9-dehydromethyltestosterone (12.5%) and oxandrolone (1.2%) exhibited high cross-reactivity. The functionality of the developed systems was verified by the successful identification of a series of 17α-methylated anabolic steroids in a set of real samples including pharmaceutical preparations seized by the Police of the Czech Republic on the black market.
- MeSH
- antisérum MeSH
- ELISA * MeSH
- kalibrace MeSH
- kongenery testosteronu analýza MeSH
- králíci MeSH
- metylace MeSH
- molekulární konformace MeSH
- sérový albumin chemie MeSH
- skot MeSH
- soudní lékařství * MeSH
- stanozolol chemie MeSH
- stereoizomerie MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Some aromatic polyketides such as dietary flavonoids have gained reputation as miraculous molecules with preeminent beneficial effects on human health, for example, as antioxidants. However, there is little conclusive evidence that dietary flavonoids provide significant leads for developing more effective drugs, as the majority appears to be of negligible medicinal importance. Some aromatic polyketides of limited distribution have shown more interesting medicinal properties and additional research should be focused on them. Combretastatins, analogues of phenoxodiol, hepatoactive kavalactones, and silymarin are showing a considerable promise in the advanced phases of clinical trials for the treatment of various pathologies. If their limitations such as adverse side effects, poor water solubility, and oral inactivity are successfully eliminated, they might be prime candidates for the development of more effective and in some case safer drugs. This review highlights some of the newer compounds, where they are in the new drug pipeline and how researchers are searching for additional likely candidates.
- MeSH
- antioxidancia * chemie terapeutické užití MeSH
- flavonoidy * chemie terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- polyketidy * chemie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Plants mentioned in this study have numerous records in traditional Peruvian medicine being used in treatment of cancer and other diseases likely to be associated with oxidative stress. Amongst the eight plant species tested, only Dysphania ambrosioides exhibited combinatory antioxidant and anti-proliferative effect on a broad spectrum of cancer cells (DPPH and ORAC values = 80.6 and 687.3 μg TE/mg extract, respectively; IC50 against Caco-2, HT-29 and Hep-G2 = 129.2, 69.9 and 130.6, respectively). Alkaloids and phenolic compounds might significantly contribute to anticancer/antioxidant activity of this plant. The results justify the traditional medicinal use of this plant. Our findings further suggest that D. ambrosioides might serve as a prospective material for further development of novel plant-based antioxidant and/or anti-proliferative agents. Detailed analysis of chemical composition together with toxicology assessments and in vivo antioxidant/anti-proliferative activity of this plant should be carried out in order to verify its potential practical use.
- MeSH
- alkaloidy analýza MeSH
- Amaranthaceae chemie MeSH
- antioxidancia chemie farmakologie MeSH
- Caco-2 buňky MeSH
- fenoly analýza MeSH
- fytogenní protinádorové látky farmakologie MeSH
- léčivé rostliny chemie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- oxidační stres MeSH
- rostlinné extrakty chemie farmakologie MeSH
- tradiční lékařství MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- Geografické názvy
- Peru MeSH
Trilobolide (Tb) is a pharmacologically interesting sesquiterpene lactone isolated from Laser trilobum (L.) Borkh. Structural relation to a sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin bring promising prospects for Tb to be used in the development of new anti-cancer drugs. As long as there are still unanswered questions regarding its investigation, a need for novel analytical tools emerge. Since immunoassays serve as one of powerful tools within the investigation of natural products, the development of indirect competitive enzyme-linked immunosorbent assay (ELISA) utilizing coating based on avidin-biotin technology is described. In our set-up of ELISA, newly synthesized biotinylated Tb served as immobilized competitor. Tb-carboxymethyloxime-bovine serum albumin (BSA) and Tb-succinoyl-BSA conjugates were used separately for immunization of rabbits. Two sets of polyclonal antibodies (RAbs) were obtained. Antibodies against Tb-succinoyl-BSA conjugate (RAb No. 206) were chosen as the best. Under optimized conditions, limit of detection and 50% intercept of our ELISA were 849pg/mL and 8.89ng/mL, respectively. The cross-reactivity (CR) was tested on 10 structurally related compounds and CR did not exceed 6.1%. The reproducibility of the system is expressed as intra- and inter-assay coefficients of variation (9.7% and 11.4%, respectively). Based on conducted experiments, we proposed the use of ELISA for quantification of Tb in complex biological matrices such as plant extracts. A method was applied to analyze three extracts obtained from different parts of L. trilobum. Data obtained were compared to those acquired by UHPLC-MS/MS. The concordance between the methods (103-87%) showed the ability of ELISA to quantify Tb.
Plants of the Amaryllidaceae family are known as producers of biologically active alkaloids. Besides these a variety of flavonoids, including flavones, chalcones and chromones, have been detected in the Amaryllidaceous plants. In this study, we have analysed 16 representatives of the family for the presence of isoflavonoids. The water/ethanolic extracts were analysed with HPLC-ESI-MS both without any pre-treatment and after immunoaffinity chromatography as a clean-up step. Four individual immunosorbents specific for biochanin A, daidzein and genistein were used. In addition, five enzyme-linked immunosorbent assays specific for the above-mentioned isoflavonoids and their derivatives have been used for the analysis of the extracts after fractionation by semi-preparative HPLC. Fifteen selected isoflavonoids were detected in the studied samples, and the amount of individual compounds ranged between ca. 0.8 and 400 ng/g of dry weight. This study extends the number of known isoflavonoid-producing families within the monocotyledonous plants.
- MeSH
- alkaloidy chemie izolace a purifikace farmakologie MeSH
- elektronová paramagnetická rezonance MeSH
- ELISA MeSH
- genistein izolace a purifikace MeSH
- isoflavony chemie izolace a purifikace farmakologie MeSH
- liliovité chemie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
