A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.
- Klíčová slova
- HDACi, anticancer agents, haematological malignancies, hydroxamic acid, inhibitors of histone deacetylases,
- MeSH
- apoptóza * účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- histondeacetylasy metabolismus MeSH
- inhibitory histondeacetylas * farmakologie chemická syntéza chemie MeSH
- kyseliny hydroxamové farmakologie chemická syntéza chemie MeSH
- kyseliny kumarové farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- proliferace buněk * účinky léků MeSH
- protinádorové látky * farmakologie chemická syntéza chemie MeSH
- screeningové testy protinádorových léčiv MeSH
- simulace molekulového dockingu MeSH
- THP-1 buňky MeSH
- vorinostat farmakologie chemická syntéza chemie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- histondeacetylasy MeSH
- inhibitory histondeacetylas * MeSH
- kyseliny hydroxamové MeSH
- kyseliny kumarové MeSH
- protinádorové látky * MeSH
- vorinostat MeSH
This work focuses on profiling N-linked glycans by capillary electrophoresis coupled to mass spectrometry using a novel fluorescent and mass spectrometry (MS) active derivatization tag. The label is based on 2-phenylpyridine bearing tertiary amine and hydrazide functionalities. It provides efficient labeling via hydrazone formation chemistry, promising fluorescence properties, and ionization efficiency in the positive ion MS mode. Electrophoretic analysis in a neutral-coated capillary allowed baseline separation of maltooligosaccharides with limits of detection in nanomolar concentrations. The developed labeling method was successfully applied to the analyses of N-linked glycans released from several glycoproteins such as bovine ribonuclease B, human immunoglobulin G, or chicken albumin.
- Klíčová slova
- Capillary electrophoresis, Glycans, Labeling, Mass spectrometry, Oligosaccharides, Phenylpyridine,
- MeSH
- elektroforéza kapilární metody MeSH
- hmotnostní spektrometrie * metody MeSH
- imunoglobulin G chemie MeSH
- kationty chemie MeSH
- kur domácí MeSH
- lidé MeSH
- polysacharidy * analýza chemie MeSH
- pyridiny * chemie MeSH
- ribonukleasy chemie MeSH
- skot MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- imunoglobulin G MeSH
- kationty MeSH
- polysacharidy * MeSH
- pyridiny * MeSH
- ribonuclease B MeSH Prohlížeč
- ribonukleasy MeSH
Several commercially available triorganotin compounds were previously found to function as agonist ligands for nuclear retinoid X receptor (RXR) molecules. Triphenyltin isoselenocyanate (TPT-NCSe), a novel selenium atom containing a derivative of triorganotin origin, was found to represent a new cognate bioactive ligand for RXRs. TPT-NCSe displayed a concentration- and time-dependent decrease in the cell viability in both human breast carcinoma MCF-7 (estrogen receptor positive) and MDA‑MB‑231 (triple negative) cell lines. Reactive oxygen species levels generated in response to TPT-NCSe were significantly higher in both carcinoma cell lines treated with TPT-NCSe when compared to mock-treated samples. Treatment with 500 nM TPT-NCSe caused a decrease in SOD1 and increased SOD2 mRNA in MCF-7 cells. The levels of SOD2 mRNA were more increased following the treatment with TPT-NCSe along with 1 μM all-trans retinoic acid (AtRA) in MCF-7 cells. An increased superoxide dismutase SOD1 and SOD2 mRNA levels were also detected in combination treatment of 500 nM TPT-NCSe and 1 μM AtRA in TPT-NCSe-treated MDA-MB-231 cells. The data have also shown that TPT-NCSe induces apoptosis via a caspase cascade triggered by the mitochondrial apoptotic pathway. TPT-NCSe modulates the expression levels of apoptosis‑related proteins, Annexin A5, Bcl‑2 and BAX family proteins, and finally, it enhances the expression levels of its cognate nuclear receptor subtypes RXRalpha and RXRbeta.
- Klíčová slova
- Apoptosis, Breast cancer, Retinoid X receptor, Triorganotin isoselenocyanates,
- MeSH
- apoptóza účinky léků MeSH
- lidé MeSH
- ligandy MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- nádory prsu * farmakoterapie metabolismus patologie MeSH
- organocínové sloučeniny * farmakologie MeSH
- organoselenové sloučeniny farmakologie chemie MeSH
- proliferace buněk účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- retinoidní X receptory metabolismus MeSH
- superoxiddismutasa 1 metabolismus genetika MeSH
- superoxiddismutasa metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ligandy MeSH
- organocínové sloučeniny * MeSH
- organoselenové sloučeniny MeSH
- reaktivní formy kyslíku MeSH
- retinoidní X receptory MeSH
- SOD1 protein, human MeSH Prohlížeč
- superoxiddismutasa 1 MeSH
- superoxiddismutasa MeSH
- superoxide dismutase 2 MeSH Prohlížeč
- triphenyltin MeSH Prohlížeč
The piperidine-based Takemoto catalyst has been successfully employed in a novel asymmetric transfer hydroxymethylation of activated isoindolinones, allowing us to prepare the enantioenriched hydroxymethylated adducts in good to excellent yields (48-96%) and enantiopurities (81:19-97:3 e.r.). To increase the reaction rate without compromising the selectivity, carefully optimized formaldehyde surrogates were employed, providing a convenient source of anhydrous formaldehyde with a base-triggered release. The substrate scope, including 34 entries, showed the considerable generality of the asymmetric transformation, and most entries exhibited complete conversions in 24-48 h. A scale-up experiment and multiple enantioselective downstream transformations were also carried out, suggesting the prospective synthetic utility of the products.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Glycosylation analysis is still challenging, not only because of the extreme structure complexity and conjugation diversity of glycans but also because of instrumental aspects such as the sensitivity limits of analyses. Therefore, glycan analysis by chromatographic methods is very often combined with fluorescence detection in addition to MS. The majority of fluorescent labeling employed before LC separation is based on 2-aminobenzamide, which has several disadvantages such as low labeling yield, poor fluorescence properties, and MS ionization efficiency. Therefore, even after several decades of development of new labels, there is still a need for new labeling tags with improved characteristics. RESULTS: We present the application of a newly synthesized fluorescent label designed for oligosaccharide and glycan analysis by high-performance liquid chromatography with fluorescence detection (HPLC/FLD). The novel hydrazide derivative of dipyrrometheneboron difluoride (BODIPY) was synthesized from 2,4-dimethylpyrrole, methyl succinyl chloride, and boron trifluoride etherate followed by a reaction with hydrazine. The synthesized label was characterized by several analytical methods including NMR, UV/Vis and fluorescence spectroscopy, and mass spectrometry. The labeling reaction via hydrazone formation chemistry was optimized by labeling of maltooligosaccharide standards. The analysis of maltohexaose labeled by BODIPY-hydrazide followed by HPLC/FLD analysis provided the limit of detection in the low tens of femtomole. The presented method based on fluorescence detection is at least 30 times more sensitive than the standard approach employing labeling by 2-aminobenzamide. In addition, the labeling method by BODIPY-hydrazide was used for N-linked glycan profiling of several glycoproteins (ribonuclease B, immunoglobulin G) by RP-HPLC/FLD as well as HILIC/FLD analysis. SIGNIFICANCE: This work represents the design, synthesis, and application of a new fluorescent label based on the BODIPY core and hydrazone formation chemistry for oligosaccharide and glycan analysis by HPLC/FLD. The proposed approach significantly improved the oligosaccharide and glycan analysis in comparison to the commonly used procedure employing 2-aminobenzamide.
- Klíčová slova
- BODIPY, Fluorescence, Glycans, Labeling, Liquid chromatography, Oligosaccharides,
- MeSH
- fluorescenční barviva chemie MeSH
- hydraziny MeSH
- hydrazony MeSH
- oligosacharidy * MeSH
- polysacharidy * analýza MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene MeSH Prohlížeč
- anthranilamide MeSH Prohlížeč
- fluorescenční barviva MeSH
- hydraziny MeSH
- hydrazony MeSH
- oligosacharidy * MeSH
- polysacharidy * MeSH
Post-translational modifications (PTMs) of biomacromolecules can be useful for understanding the processes by which a relatively small number of individual genes in a particular genome can generate enormous biological complexity in different organisms. The proteomes of barley and the brewing process were investigated by different techniques. However, their diverse and complex PTMs remain understudied. As standard analytical approaches have limitations, innovative analytical approaches need to be developed and applied in PTM studies. To make further progress in this field, it is necessary to specify the sites of modification, as well as to characterize individual isoforms with increased selectivity and sensitivity. This review summarizes advances in the PTM analysis of barley proteins, particularly those involving mass spectrometric detection. Our focus is on monitoring phosphorylation, glycation, and glycosylation, which critically influence functional behavior in metabolism and regulation in organisms.
- Klíčová slova
- barley, mass spectrometry, post-translational modification, protein,
- MeSH
- fosforylace MeSH
- glykosylace MeSH
- ječmen (rod) * genetika MeSH
- posttranslační úpravy proteinů MeSH
- proteom chemie MeSH
- proteomika metody MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- proteom MeSH
Intensive investigation for novel antiproliferative and cytotoxic effective chemical compounds is currently concentrated on structurally modified agents of natural or synthetic source. The selenium derivative of triorganotin compound, triphenyltin isoselenocyanate (TPT-NCSe) caused higher cytotoxicity in hormone sensitive MCF 7 (IC 50-250 nM) in comparison with triple-negative MDA-MB-231 breast carcinoma cell line (IC 50-450 nM) as determined by MTT assay. Measurement of DNA damage showed presence of crosslinks in both cell lines treated by increasing TPT-NCSe concentrations. This compound decreased mitochondrial membrane potential shown by JC-1 staining in a concentration-dependent manner in both cell lines. Activation of caspases-3/7 was observed in MDA-MB-231 cells and was significant only by concentrations causing significant level of crosslinks. On the other hand, migration assay revealed inhibitory effect of viability keeping 100 nM concentration of TPT-NCSe on migration of MDA-MB-231 cells. Our data has shown that this selenium containing triorganotin molecule exerts DNA damage-linked antineoplastic activity in breast carcinoma cell lines studied.
- Klíčová slova
- Apoptosis, Breast cancer, Cytotoxicity, DNA crosslinks, Migration, Triorganotin isoselenocyanates,
- MeSH
- apoptóza MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- nádory prsu * farmakoterapie MeSH
- organocínové sloučeniny MeSH
- organoselenové sloučeniny MeSH
- proliferace buněk MeSH
- protinádorové látky * chemie farmakologie MeSH
- selen * farmakologie MeSH
- triple-negativní karcinom prsu * metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- isoselenocyanate MeSH Prohlížeč
- organocínové sloučeniny MeSH
- organoselenové sloučeniny MeSH
- protinádorové látky * MeSH
- selen * MeSH
- triphenyltin MeSH Prohlížeč
An efficient and versatile synthesis of the naturally occurring C-prenylated stilbenoid methyl ethers and their synthetic analogues is presented. The synthesis represents a six step convergent process including an optimised C-prenylation method. Furthermore, during the demethylation process, six new dihydro-benzopyranyl derivatives were obtained and isolated.
- Publikační typ
- časopisecké články MeSH
The knowledge of the structure, function, and abundance of specific proteins related to the EMT process is essential for developing effective diagnostic approaches to cancer with the perspective of diagnosis and therapy of malignancies. The success of all-trans retinoic acid (ATRA) differentiation therapy in acute promyelocytic leukemia has stimulated studies in the treatment of other tumors with ATRA. This review will discuss the impact of ATRA use, emphasizing epithelial-mesenchymal transition (EMT) proteins in breast cancer, of which metastasis and recurrence are major causes of death.
- Klíčová slova
- ATRA, EMT, breast cancer, protein,
- MeSH
- epitelo-mezenchymální tranzice * MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádorové proteiny agonisté metabolismus MeSH
- nádory prsu metabolismus mortalita patologie MeSH
- receptory kyseliny retinové agonisté metabolismus MeSH
- tretinoin metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- nádorové proteiny MeSH
- receptory kyseliny retinové MeSH
- tretinoin MeSH
We have identified a novel one-pot method for the synthesis of β-amino alcohols, which is based on C-H bond hydroxylation at the benzylic α-carbon atom with a subsequent nitrile or amide functional group reduction. This cascade process uses molecular oxygen as an oxidant and sodium bis(2-methoxyethoxy)aluminum hydride as a reductant. The substrate scope was examined on 30 entries and, although the respective products were provided in moderate yields only, the above simple protocol may serve as a direct and powerful entry to the sterically congested 1,2-amino alcohols that are difficult to prepare by other routes. The plausible mechanistic rationale for the observed results is given and the reaction was applied to a synthesis of a potentially bioactive target.
- Publikační typ
- časopisecké články MeSH
