We tested the effect of substituents at the (1) C3 ́, C3 ́N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3 ́ and C3 ́N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.
- MeSH
- benzoáty farmakologie chemie MeSH
- chemorezistence * účinky léků MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- nádory prsu farmakoterapie patologie MeSH
- nádory vaječníků farmakoterapie patologie MeSH
- P-glykoproteiny * metabolismus genetika MeSH
- paclitaxel farmakologie MeSH
- protinádorové látky farmakologie chemie MeSH
- taxoidy farmakologie chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Pluripotent stem cells of the bone marrow are stimulated by different cytokines to proliferation and differentiation into various types of blood cells. These cytokines are mostly glycoproteins. Erythropoietin stimulates stem cells to the formation of erythrocytes while colony-stimulating factors cause the formation of different types of white blood cells. Stem cell factors play an important role in the maintenance and survival of blood cells of all types. Thrombopoietin stimulates stem cells to proliferation and formation of blood platelets. Granulocyte colony-stimulating factor is probably the most important drug in use. It stimulates stem cells to the formation of neutrophile granulocytes. It is often used in recombinant forms such as filgrastim in the treatment of neutropenia in cancer chemotherapy or AIDS. Its pegylated conjugates such as pegfilgrastim are also available. Its activity can be supported by plerixafor, a small molecule - bicyclam derivative acting as an indirect agonist of stem cells factor. It acts as an antagonist of CXCR4 receptor activation of which brakes hematopoiesis. The treatment of conditions accompanied by thrombocytopenia such as idiopathic thrombocytopenic purpura is currently not performed by thrombopoietin but synthetic agonists of its receptor are preferred. Romiplostim is a peptibody. It consists of a protein part interacting with the thrombopoietin receptor which is, however, different from thrombopoietin, and of Fc fragment of immunoglobulin G1. In contrast, small molecule thrombopoietin receptor agonists represented by eltrombopag can be given orally unlike all of the above.
- MeSH
- benzoáty chemie farmakologie MeSH
- buněčná diferenciace účinky léků MeSH
- faktory stimulující kolonie farmakologie MeSH
- hydraziny chemie farmakologie MeSH
- knihovny malých molekul chemie farmakologie MeSH
- leukocyty mononukleární cytologie účinky léků metabolismus MeSH
- lidé MeSH
- pyrazoly chemie farmakologie MeSH
- receptory thrombopoetinu agonisté metabolismus MeSH
- růstový faktor kmenových buněk farmakologie MeSH
- trombocyty cytologie metabolismus MeSH
- trombopoéza účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (pKa) and lipophilicity index (log P) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations.
- MeSH
- acetylcholinesterasa MeSH
- aktivace enzymů účinky léků MeSH
- benzoáty chemická syntéza chemie farmakologie MeSH
- butyrylcholinesterasa MeSH
- chemické modely MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- kvartérní amoniové sloučeniny chemická syntéza chemie farmakologie MeSH
- molekulární modely * MeSH
- soli chemie MeSH
- techniky syntetické chemie * MeSH
- vazba proteinů MeSH
- Publikační typ
- časopisecké články MeSH
Benzoate 1,2-dioxygenase (BDO) of Rhodococcus opacus 1CP, which carried out the initial attack on benzoate, was earlier shown to be the enzyme with a narrow substrate specificity. A kinetics of interaction between benzoate 1,2-dioxygenase and substituted benzoates was assessed taking into account the enlarged list of the type of inhibition and using whole cells grown on benzoate. The type of inhibition was determined and the constants of a reaction of BDO with benzoate in the presence of 2-chlorobenzoate (2CBA), 3,5-dichlorobenzoate (3,5DCBA), and 3-methylbenzoate (3MBA) were calculated. For 2CBA and 3MBA, the types of inhibition were classified as biparametrically disсoordinated inhibition and transient inhibition (from activation towards inhibition), respectively. The process of not widely recognized pseudoinhibition of a BDO reaction with benzoate by 3,5DCBA was assessed by the vector method for the representation of enzymatic reactions. Ki value was determined for 2CBA, 3MBA, and 3,5DCBA as 337.5, 870.3, and 14.7 μM, respectively.
Nine new dihydrochloride salts of 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-alkoxyethoxybenzoates were designed and synthesized. The physicochemical properties such as lipophilicity index (log kw) and dissociation constant (pKa) were experimentally determined and compared to the software calculated data. The lipophilicity index was determined by means of reversed-phase high performance liquid chromatography (RP-HPLC). The pKa values were determined by means of capillary zone electrophoresis. The "drug-likeness" properties according to the Lipinski Rule of Five and prediction of possible blood-brain barrier penetration were computed and discussed.
- MeSH
- benzoáty chemická syntéza chemie MeSH
- chemické jevy MeSH
- chromatografie s reverzní fází metody MeSH
- hydrofobní a hydrofilní interakce MeSH
- koncentrace vodíkových iontů MeSH
- lipidy chemie MeSH
- software * MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
New butyltin complexes with 2-sulfobenzoic acid: [Sn(C4H9)2{O3SC6H4COO-2}(H2O)]·(C2H5OH) (DBTsbz), [Sn(C4H9)3{O3SC6H4COOH-2}] (TBTsbz) and [Sn2(C4H9)6{μ-O3SC6H4COO-2}] (DTBTsbz) are very effective cytotoxic agents against tumor cells. The molecular interaction of these complexes with lipid membranes and DNA has been investigated. The IR spectra and changes of (1)H, (13)C chemical shifts suggest that SO3 and COO groups of 2-sulfobenzoato ligand interact with O atom of glycerin fragment of DPPC. Moreover, the compounds form Sn-OP bonds with phosphate groups of DPPC, which was shown by the lower frequency shift of the νs(PO2(-)) and νas(PO2(-)) band, by change of (31)P NMR signals and by DFT calculation. Another possibility is the interaction of the phosphate group of DPPC owing to formation of hydrogen bond O-H…O-P between water molecule coordinated to Sn and oxygen atom from the phosphate group. Using TCSPC-FCS we characterized DNA supramolecular assemblies' formation upon increasing TBTsbz, DTBTsbz and DBTsbz concentration. Diffusion time, lifetime and particle number changes are altered systematically with increasing Ccomp/CDNAbp ratio in following effectiveness order DBTsbz > TBTsbz > DTBTsbz. From those parameters we can conclude that all these compounds lead to a change of DNA winding, strand but not to DNA compaction. Investigated compounds show very high cytotoxic activity against cancer cell lines. All compounds exhibit efficient in vitro antitumor activity toward Jurkat (T-cell leukemia), CL-1 (T-lymphoblastoid cell line), GL-1 (B cell lymphoma cell line) and D-17 (canine osteosarcoma). The DBTsbz is more effective then carboplatin against canine osteosarcoma.
- MeSH
- benzensulfonáty chemie farmakologie MeSH
- benzoáty chemie farmakologie MeSH
- DNA chemie metabolismus MeSH
- konformace nukleové kyseliny účinky léků MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- lipidové dvojvrstvy chemie metabolismus MeSH
- molekulární modely MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie MeSH
- organocínové sloučeniny chemie farmakologie MeSH
- protinádorové látky chemie farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Five new 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-propoxybenzoates were designed and synthesized as potential dual antihypertensive agents. The compounds were prepared as free bases and subsequently transformed to hydrochloride salts. The position of protonation of nitrogen atoms in the piperazine ring of hydrochloride salts was determined by means of (13)C-CP/MAS and (15)N-CP/MAS NMR and IR spectroscopy. Using these solid-state analytical techniques, it was found that both nitrogen atoms were protonated when excess hydrogen chloride was used for preparation of salts. On the other hand, when the equimolar amount of hydrogen chloride was used, piperazine nitrogen substituted by aryl was protonated.
- MeSH
- antihypertenziva chemická syntéza chemie MeSH
- benzoáty chemická syntéza chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- piperaziny chemie MeSH
- soli chemie MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- Publikační typ
- časopisecké články MeSH
Based on the previously described antimicrobial activity of salicylanilide derivatives, we designed and synthesized novel 2-(phenylcarbamoyl)phenyl 4-substituted benzoates. The most active salicylanilides were selected for esterification by various 4-substituted benzoic acids. These compounds were evaluated in vitro against Mycobacterium tuberculosis, including multidrug-resistant strains, nontuberculous mycobacteria (Mycobacterium avium and Mycobacterium kansasii), and eight bacterial and fungal strains. We also investigated the cytostatic and cytotoxic actions of the esters. The minimum inhibitory concentrations (MICs) against mycobacteria ranged from 0.125 to 8μM. Interestingly, the drug-resistant strains exhibited the highest susceptibility without any cross-resistance with established drugs. 4-Bromo-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-nitrobenzoate showed the most potent inhibition with MIC values ranging from 0.25 to 2μM. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited by two derivatives with MIC values of at least 0.49μM, whereas Gram-negative bacteria and most of the tested fungi did not display any marked susceptibility. Benzoates exhibited no cytotoxicity at concentrations up to 50μM but most caused significant cytostasis with IC50 values lower than 10μM. Some cytotoxicity-based selectivity indexes for drug-susceptible and drug-resistant M. tuberculosis as well as Staphylococci were higher than 100. These values indicate that some of these derivatives are promising candidates for future research.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- antifungální látky chemická syntéza chemie farmakologie MeSH
- Bacteria účinky léků MeSH
- bakteriální infekce farmakoterapie MeSH
- benzoáty chemická syntéza chemie farmakologie MeSH
- houby účinky léků MeSH
- lidé MeSH
- multirezistentní tuberkulóza farmakoterapie MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- Mycobacterium účinky léků MeSH
- mykobakteriózy farmakoterapie MeSH
- mykózy farmakoterapie MeSH
- tuberkulóza farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The 22 amphetamine-derived synthetic drugs (ADSDs), mostly cathinones, were examined by gas chromatography with mass spectrometry using two different derivatization methods with (i) heptafluorobutyric anhydride (HFBA) and (ii) pentafluorobenzoyl chloride (PFBCl). Both developed derivatization approaches were evaluated and compared for urine and serum samples. Extraction procedures proved to give satisfactory results with regard to recoveries and extract purity, even though both derivatization methods reached acceptable sensitivity for the intended use. The derivatization with PFBCl showed better results with respect to retention and response stability, thus the PFBCl method was selected for validation. Calibration curves were linear over the tested concentration range of 20-1,000 ng/mL with the R(2) values ranging from 0.994 to 0.998. Intra- and interday precisions and accuracies were within 20% for all concentrations in the linear range. The limit of detection was determined to be lower than 2 ng/mL for all 22 analytes. The method proved to be a useful analytical tool in the course of systematic toxicological analysis.
- MeSH
- amfetaminy analýza krev moč MeSH
- benzoáty chemie MeSH
- fluorokarbony chemie MeSH
- kalibrace MeSH
- lidé MeSH
- limita detekce MeSH
- metody pro přípravu analytických vzorků MeSH
- nové syntetické drogy analýza MeSH
- odhalování abúzu drog metody MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí * MeSH
- senzitivita a specificita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
N-(α-ketoacyl)anthranilic acids reacted with phenylhydrazinium chloride in boiling acetic acid to afford 2-(indol-2-carboxamido)benzoic acids in good to excellent yields and 2-indolyl-3,1-benzoxazin-4-ones as by-products. The formation of the latter products could easily be suppressed by a hydrolytic workup. Alternatively, by increasing the reaction temperature and/or time, 2-indolyl-3,1-benzoxazin-4-ones can be obtained exclusively. Optimisations of the reaction conditions as well as the scope and the course of the transformations were investigated. The products were characterized by (1)H, (13)C and (15)N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments ((1)H-(1)H gs-COSY, (1)H-(13)C gs-HSQC, (1)H-(13)C gs-HMBC) with (1)H-(15)N gs-HMBC as a practical tool to determine (15)N NMR chemical shifts at the natural abundance level of (15)N isotope.
