activated borane
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Surface of ultra-high-molecular-weight polyethylene (UHMWPE) was modified by chemical methods. Surface was firstly activated by Piranha solution and then grafted with selected amino-compounds (cysteamine, ethylenediamine or chitosan). The next step was grafting of some borane cluster compounds, highly fluorescent borane hydride cluster anti-B18H22 or its thiolated derivative 4,4'-(HS)2-anti-B18H20. Polymer foils were studied using various methods to characterize surface chemistry (X-ray photoelectron spectroscopy), roughness and morphology (atomic force microscopy, scanning electron microscopy), chemistry and polarity (electrokinetic analysis), wettability (goniometry) and photophysical properties (UV-Vis spectroscopy) before and after modification steps. Subsequently some kinds of antimicrobial tests were performed. Immobilization of anti-B18H22 in small quantities onto UHMWPE surface leads to materials with a luminescence. Samples grafted with borane clusters showed significant inhibition of growth for gram-positive bacteria (S. epidermidis). These approaches can be used for (i) luminophores on the base of polymers nanocomposites development and/or (ii) preparation of materials with antimicrobial effects.
HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition.
- MeSH
- aspartátové endopeptidasy chemie MeSH
- borany farmakologie chemická syntéza chemie MeSH
- financování organizované MeSH
- HIV-proteasa chemie MeSH
- inhibitory HIV-proteasy farmakologie chemická syntéza chemie MeSH
- krystalografie rentgenová MeSH
- kvantitativní vztahy mezi strukturou a aktivitou MeSH
- racionální návrh léčiv MeSH
The development of 1,8-naphthalimide derivatives as DNA-targeting anticancer agents is a rapidly growing area and has resulted in several derivatives entering into clinical trials. One of original recent developments is the use of boron clusters: carboranes and metallacarboranes in the design of pharmacologically active molecules. In this direction several naphthalimide-carborane and metallacarborane conjugates were synthesized in the present study. Their effect on a cancer cell line - cytotoxicity, type of cell death, cell cycle, and ROS production were investigated. The tested conjugates revealed different activities than the leading members of the naphthalimides family, namely mitonafide and pinafide. These derivatives could induce G0/G1 arrest and promote mainly apoptosis in HepG2 cell line. Our investigations demonstrated that the most promising molecule is N-{[2-(3,3'-commo-bis(1,2-dicarba-3-cobalta(III)-closo-dodecaborate-1-yl)ethyl]-1'-aminoethyl)}-1,8-naphthalimide] (17). It was shown that 17 exhibited cytotoxicity against HepG2 cells, activated cell apoptosis, and caused cell cycle arrest in HepG2 cells. Further investigations in HepG2 cells revealed that compound 17 can also induce ROS generation, particularly mitochondrial ROS (mtROS), which was also proved by increased 8-oxo-dG level in DNA. Additionally to biological assays the interaction of the new compounds with ct-DNA was studied by CD spectra and melting temperature, thus demonstrating that these compounds were rather weak classical DNA intercalators.
- MeSH
- borany chemie farmakologie MeSH
- buněčné linie MeSH
- buňky Hep G2 MeSH
- DNA nádorová účinky léků MeSH
- lidé MeSH
- molekulární struktura MeSH
- naftalimidy chemie farmakologie MeSH
- organokovové sloučeniny chemická syntéza chemie farmakologie MeSH
- oxidační stres účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- vazebná místa MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A new type of high performance liquid chromatography (HPLC) stationary phase was prepared, and its chromatographic properties were evaluated. The sorbent was composed of metallacarborane covalently bound to silica. Because of the chemical structure of the immobilized metallacarborane, the synthesized stationary phase was able to interact with nonpolar analytes via hydrophobic interactions. The chromatographic behavior of several low-molecular-weight hydrocarbons on the sorbent under typical reversed-phase conditions was compared with octadecyl-, sulfo phenyl- and aminopropyl-modified silica stationary phases. Moreover, as a consequence of the synthetic protocol employed, the immobilization of the metallacarborane led to the development of a zwitterionic chemically bonded phase, which demonstrated excellent resistance to "phase collapse" in a 100% aqueous environment. Finally, preliminary experiments indicated that the new stationary phase has the potential for utilization in hydrophilic interaction chromatography (HILIC) mode for the separation of polar compounds.
- MeSH
- acetonitrily chemie MeSH
- benzenové deriváty chemie MeSH
- borany chemie MeSH
- chromatografie s reverzní fází MeSH
- hydrofobní a hydrofilní interakce MeSH
- kobalt chemie MeSH
- lineární modely MeSH
- oxid křemičitý chemie MeSH
- Ramanova spektroskopie MeSH
- reprodukovatelnost výsledků MeSH
- vysokoúčinná kapalinová chromatografie přístrojové vybavení metody MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Carbonic anhydrase IX (CAIX) is a transmembrane enzyme that regulates pH in hypoxic tumors and promotes tumor cell survival. Its expression is associated with the occurrence of metastases and poor prognosis. Here, we present nine derivatives of the cobalt bis(dicarbollide)(1-) anion substituted at the boron or carbon sites by alkysulfamide group(s) as highly specific and selective inhibitors of CAIX. Interactions of these compounds with the active site of CAIX were explored on the atomic level using protein crystallography. Two selected derivatives display subnanomolar or picomolar inhibition constants and high selectivity for the tumor-specific CAIX over cytosolic isoform CAII. Both derivatives had a time-dependent effect on the growth of multicellular spheroids of HT-29 and HCT116 colorectal cancer cells, facilitated penetration and/or accumulation of doxorubicin into spheroids, and displayed low toxicity and showed promising pharmacokinetics and a significant inhibitory effect on tumor growth in syngenic breast 4T1 and colorectal HT-29 cancer xenotransplants.
- MeSH
- amidy chemie MeSH
- biologický transport účinky léků MeSH
- borany chemie farmakologie MeSH
- doxorubicin metabolismus MeSH
- inhibitory karboanhydras chemie farmakologie MeSH
- karboanhydrasa IX chemie metabolismus MeSH
- katalytická doména MeSH
- lidé MeSH
- molekulární modely MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- racionální návrh léčiv MeSH
- synergismus léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The diastereomeric substituted 2H-dihydropyran derivatives 2b and 3b were obtained by the stereoselective cycloaddition of (E)-4-(tetra-O-benzyl-?-D-galactopyranosyl)-1-(thiazol-2-yl)but-2-en-1-one (1) with either of the enantiomeric chiral vinyl ethers (R)-4 or (S)-4. Reduction of the ester group, transformation of the thiazole ring into an aldehyde group and reaction with an excess of borane afforded the final C-(1›3)-disaccharide structures. The obtained C-(1›3)-disaccharides, containing an L- or D-deoxy-arabino-hexopyranose moiety at the reducing end, were characterized as peracetylated methyl glycosides 9a, 9b and 12a, 12b.
Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, d-galactal and d-allal-derived vinyl epoxides (VEβ and VEα) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1β and 1α. Ligand exchange with [Ru(C2O4)(η6-p-cymene)(H2O)] gave the glycoconjugated complexes Ru1β and Ru1α which were subsequently dihydroxylated with OsO4/N-methylmorpholine N-oxide to Ru2β and Ru2α containing O-benzyl d-mannose and d-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-β-d-glucopyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3∙BH3. Zemplén deacylation with MeONa/MeOH gave the deprotected d-glucopyranoside derivative 4∙BH3. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3∙BH3 and 4∙BH3 with [Ru(C2O4)(η6-p-cymene)(H2O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1β, Ru1α). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the β anomer. However, Ru1β, Ru1α did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1β, inducing cell death by apoptosis.
- MeSH
- fosfiny MeSH
- komplexní sloučeniny * chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků * MeSH
- protinádorové látky * chemie MeSH
- ruthenium * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We studied cadmium toxicity in murine hepatocytes in vitro. Cadmium effects on intracellular free Ca2+ concentration ([Ca2+]i) were assayed, using a laser scanning confocal microscope with a fluorescent probe, Fluo-3/AM. The results showed that administration of cadmium chloride (CdCl2, 5, 10, 25 µM) resulted in a dose-dependent decrease of hepatocyte viability and an elevated aspartate aminotransferase (AST) activity in the culture medium (p<0.05 for 25 µM CdCl2 vs. control). Significant increases of lactate dehydrogenase (LDH) activities in 10 and 25 µM CdC12-exposed groups were observed (p<0.05 and p<0.01, respectively). A greatly decreased albumin content and a more malondialdehyde (MDA) formation also occurred after CdC12 treatment. The Ca2+ concentrations in the culture medium of CdCl2-exposed hepatocytes were significantly decreased, while [Ca2+]i appeared to be significantly elevated (p<0.05 or p<0.01 vs. control). We found that in Ca2+-containing hydroxyethyl piperazine ethanesulfonic acid-buffered salt solution (HBSS) only, CdCl2 elicited [Ca2+]i increases, which comprised an initially slow ascent and a strong elevated phase. However, in Ca2+-containing HBSS with addition of 2-aminoethoxydiphenyl borane (2-APB), CdCl2 caused a mild [Ca2+]i elevation in the absence of an initial rise phase. Removal of extracellular Ca2+ showed that CdCl2 induced an initially slow [Ca2+]i rise alone without being followed by a markedly elevated phase, but in a Ca2+-free HBSS with addition of 2-APB, CdCl2 failed to elicit the [Ca2+]i elevation. These results suggest that abnormal Ca2+ homeostasis due to cadmium may be an important mechanism of the development of the toxic effect in murine hepatocytes. [Ca2+]i elevation in acutely cadmium-exposed hepatocytes is closely related to the extracellular Ca2+ entry and an excessive release of Ca2+ from intracellular stores.
- MeSH
- chlorid kademnatý škodlivé účinky toxicita MeSH
- finanční podpora výzkumu jako téma MeSH
- hepatocyty cytologie chemie účinky léků MeSH
- homeostáza fyziologie účinky léků MeSH
- kadmium chemie škodlivé účinky toxicita MeSH
- konfokální mikroskopie metody využití MeSH
- myši inbrední ICR anatomie a histologie krev MeSH
- poruchy metabolismu vápníku etiologie komplikace MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
... reactions with electrophiles 473 -- Electrophilic substitution on phenols 479 -- A nitrogen lone pair activates ... ... reactivity pattern of radicals is quite different from that of polar reagents 997 -- Alkyl radicals from boranes ... ... an alkene 1079 -- Cross-coupling of organometallics and halides 1082 -- Allylic electrophiles are activated ...
Second edition xxv, 1234 stran : ilustrace ; 28 cm
- Konspekt
- Organická chemie
- NLK Obory
- chemie, klinická chemie
- NLK Publikační typ
- učebnice vysokých škol
... Boran G., Sinnott M., Alexander D., Crimson J., O’Moore R. ... ... Implementing of an Audit of the Theatre Activity by the Anaesthetic Department in Derby. ...
1589 s. : il. ; 24 cm
