Search

The rehabilitation after pediatric brain tumors is a pressing issue in current neuro-oncology. The purpose of this study was to reveal the peculiarities of postural stability in pediatric posterior fossa tumor survivors as compared to the healthy controls. Additionally, we aimed to determine the feasibility of the balance biofeedback training for these patients. We measured 6 postural stability parameters with the eyes opened and closed in 35 patients and 25 healthy controls aged 7–17. Further, the patients were divided into two groups: the intervention and waitlist. The intervention group was the first to undergo a 2-week biofeedback training designed to enhance balance control, while the waitlist group performed only the usual exercises. Then the groups were interchanged. Pre- and post-stability scores were measured in each condition. The current results suggest the pronounced deficiency of stability in the patients. Their results in both opened and closed eyes conditions were similar. The post-training measurements revealed that some stability parameters were improved: ellipse square and mean root square oscillations in the frontal and sagittal planes. The patients predictably demonstrated the significantly worse stability measurements as compared to the healthy controls. Moreover, they were shown not to use visual information to correct postural balance thus prompting us to assume severe deficits of the eye movements control due to the cerebellar pathology. This specificity, as well as the post-training significant improvement, emphasizes the clinical necessity to consider them when designing the rehabilitation protocols for posterior fossa tumor survivors. • Pediatric posterior fossa tumor survivors showed a decreased postural stability. • Cerebellum lesion prevents patients from using visual information for stability. • The biofeedback training aimed at enhancing stability was proved to be feasible. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low selectivity. Targeted drug delivery is a promising approach to decrease side effects of therapy. Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer cells while low level of expression is observed in normal cells. In this study we describe the development of Glu-urea-Lys based PSMA-targeting conjugates with paclitaxel. A series of new PSMA targeting conjugates with paclitaxel was designed and synthesized. The cytotoxicity of conjugates was evaluated against prostate (LNCaP, 22Rv1 and PC-3) and non-prostate (Hek293T, VA13, A549 and MCF-7) cell lines. The most promising conjugate 21 was examined in vivo using 22Rv1 xenograft mice model. It demonstrated good efficiency comparable with paclitaxel, while reduced toxicity. 3D molecular docking study was also performed to understand underlying mechanism of binding and further optimization of the linker substructure and conjugates structure for improving the target affinity. These conjugates may be useful for further design of novel PSMA targeting delivery systems for PC. [ABSTRACT FROM AUTHOR]

G4-stabilizing ligands are now being considered as anticancer, antiviral and antibacterial agents. Phenoxazine is a promising scaffold for the development of G4 ligands. Here, we profiled two known phenoxazine-based nucleoside analogs and five new nucleoside and non-nucleoside derivatives against G4 targets from telomere repeats and the KIT promoter region. Leading new derivatives exhibited remarkably high G4-stabilizing effects (comparable or superior to the effects of the commonly used selective G4 ligands PDS and NMM) and selectivity toward G4s over duplex (superior to BRACO-19). All phenoxazine-based ligands inhibited cellular metabolic activity. The phenoxazine derivatives were particularly toxic for lung adenocarcinoma cells A549' and human liver cancer cells HepG2 (CC 50 of the nucleoside analogues in the nanomolar range), but also affected breast cancer cells MCF7, as well as immortalized fibroblasts VA13 and embryonic kidney cells HEK293t (CC 50 in the micromolar range). Importantly, the CC 50 values varied mostly in accordance with G4-binding affinities and G4-stabilizing effects, and the phenoxazine derivatives localized in the cell nuclei, which corroborates G4-mediated mechanisms of action. • Phenoxazine-based derivatives were probed as G4 ligands. • Some derivatives exhibited remarkably high G4-stabilizing effects and selectivity. • All phenoxazine-based ligands inhibited cellular metabolic activity. • The ligands were particularly toxic for lung adenocarcinoma cells. • Localization in the cell nuclei corroborated G4-mediated mechanisms of action. [ABSTRACT FROM AUTHOR]

Background: The bulk of relevant studies compare individual or very few sports and on small samples of athletes. This requires extensive analysing postural stability in various sports.Research Question: The main objective of our study was to identify the features of postural stability in a normal vertical stance in athletes of various kinds.Methods: This study compares postural stability in a normal bipedal stance with eyes open (EO) and eyes closed (EC) conditions among athletes (n = 936, age: 6-47 years) from different sports and performance level. Postural stability was measured through the center of pressure (COP) sway area (AS) and velocity (VCP) while standing quietly in a normal bipedal position with EO and EC on a stabiloplatform (50 Hz).Results: The order of VCP-EO increase in athletes compared to Control was as follows: Shooting (-11.3 %, p < .0001) < Football (-10.4 %, p < .0001) < Boxing (-8.7 %, p < .0001) < Cross-Country Skiing (-7.2 %, p < .0001) < Gymnastics (-7.0 %, p < .0001) < Running (-6.9 %, p < .0001) < Team Games Played with Hands (-6.8 %, p < .0001) < Wrestling (-6.3 %, p < .0001) < Tennis (-5.5 %, p = .0004) < Alpine Skiing (-5.4 %, p = .002) < Rowing (-5.0 %, p = .194) < Speed Skating (-4.7 %, p = .004) < Figure Skating (-3.6 %, p = .034) < Control.Significance: Practicing any kind of sport was associated with increased postural stability in normal bipedal stance. This is the first study that provides reference values of COP sway and velocity with and without visual control on a stable force platform for different sport groups. [ABSTRACT FROM AUTHOR]

The aromatic polyketide tetracenomycin X (TcmX) was recently found to be a potent inhibitor of protein synthesis; its binding site is located in a unique locus within the tunnel of the large ribosomal subunit. The distinct mode of action makes this relatively narrow class of aromatic polyketides promising for drug development in the quest to prevent the spread of drug-resistant pathogens. Here we report the isolation and structure elucidation of a novel natural tetracenomycin X congener – 6-hydroxytetraceonomycin X (6-OH-TcmX). In contrast to TcmX, 6-OH-TcmX exhibited lower antimicrobial and cytotoxic activity, but comparable in vitro protein synthesis inhibition ability. A survey on spectral properties of tetracenomycins revealed profound differences in both UV-absorption and fluorescence spectra between TcmX and 6-OH-TcmX, suggesting a significant influence of 6-hydroxylation on the tetracenomycin X chromophore. Nonetheless, characteristic spectral properties of tetracenomycins make them suitable candidates for semi-synthetic drug development (e.g., for targeted delivery, chemical biology, or cell imaging). [Display omitted] • Hydroxylated tetracenomycin X is produced by the Amycolatopsis sp. A23 strain. • 6-Hydroxylation reduces both antimicrobial and cytotoxic activity of tetracenomycin X. • 6-Hydroxylation significantly alters the tetracenomycin X chromophore. • UV–Vis spectra of tetracenomycins are dependent on solvent and pH. • Activity is impaired, but not due to lower protein synthesis inhibition ability. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), has recently emerged as a prominent biomarker of prostate cancer (PC) and as an attractive protein trap for drug targeting. At the present time, several drugs and molecular diagnostic tools conjugated with selective PSMA ligands are actively evaluated in different preclinical and clinical trials. In the current work, we discuss design, synthesis and a preliminary biological evaluation of PSMA-specific small-molecule carrier equipped by Doxorubicin (Dox). We have introduced an unstable azo-linker between Dox and the carrier hence the designed compound does release the active substance inside cancer cells thereby providing a relatively high Dox concentration in nuclei and a relevant cytotoxic effect. In contrast, we have also synthesized a similar conjugate with a stable amide linker and it did not release the drug at all. This compound was predominantly accumulated in cytoplasm and did not cause cell death. Preliminary in vivo evaluation has showed good efficiency for the degradable conjugate against PC3-PIP(PSMA+)-containing xenograft mine. Thus, we have demonstrated that the conjugate can be used as a template to design novel analogues with improved targeting, anticancer activity and lower rate of potential side effects. 3D molecular docking study has also been performed to elucidate the underlying mechanism of binding and to further optimization of the linker area for improving the target affinity. [ABSTRACT FROM AUTHOR]

A novel strain of Actinomycetes was isolated from the body of an ant (Camponotus vagus Scopoli) and its genetic and morphological properties were characterized. The 16S rDNA gene sequence analysis of the isolate revealed its high phylogenetic relationship with type strains of Streptomyces violaceochromogenes NBRC 13100T. As a result of antimicrobial activity assessment, it was found that the fermentation broth of the isolated strain both inhibited the growth and induced the SOS response in E. coli BW25113 ΔtolC strain cells. Using bioassay-guided fractionation, mass spectrometric and NMR analyses we identified the active compound to be nybomycin, a previously described antibiotic. Here we report for the first time Streptomyces producer of nybomycin in association with carpenter ants and demonstrate cytotoxic activity of nybomycin against human cell lines. • Streptomyces sp. isolated from carpenter ants produces antibiotic nybomycin. • Nybomycin demonstrates cytotoxic activity against human cell lines (fibroblasts and lung cancer). • Nybomycin, like fluoroquinolones, induces SOS-response in E.coli cells. [ABSTRACT FROM AUTHOR]

New copper(II) complexes of 2-alkylthio-5-arylmethylene-4H-imidazolin-4-ones: (5Z)-2-(methylsulfanyl)-3-(prop-2-en-1-yl)-5-(pyridin-2-ylmethylidene)-3,5-dihydro-4H-imidazol-4-one) ( 1a ), (5Z,5′Z)-2,2′-(ethan-1,2-diyldisulfanyldiyl)bis(5-(2-pyridilmethylen)-3-allyl-3,5-dihydo-4Н-imidazole-4-one) ( 2a ) and (5Z,5′Z)-3,3′-hexan-1,6-diylbis[5-(2-pyridilmethylen)-2-methylthiotetrahydro-4Н-imidazole-4-one)] ( 3a ) were synthesized as possible anticancer drugs. Their structures were characterized by 1 H NMR spectroscopy, elemental analysis, and X-ray crystallography. The composition of the complexes were found for 1a (Cu:L = 1 : 1 ), 2a (Cu:L = 2 : 1 ), and 3a (Cu:L = 2 : 1 ). The chelation constants were found by competitive complexation with ethylenediamine tetraacetate: 1a (6.7 ± 0.6) × 10 15 M − 1 , 2a = (4.9 ± 0.4) × 10 19 M − 2 , and 3a (5.7 ± 0.5) × 10 19 M − 2 . Supramolecular binding with calf thymus DNA by competitive ethidium bromide quenching was made for complex 2a as the most promising anticancer model, the Stern–Volmer constants were found to be K SV = (8.0 ± 0.4) × 10 6 M − 1 , K q = (6.5 ± 0.4) × 10 5 M − 1 . The binding of the complex 2a to BSA was made by the Scatchard method, the value of the constant is K b = (1.9 ± 0.2) × 10 6 M − 1 . [ABSTRACT FROM AUTHOR]

A convenient and efficient catalytic procedure for the selective S -arylation of 2-thioxoimidazolidin-4-ones to give novel S -aryl substituted 2-thiohydantoins under mild reaction conditions using arylboronic acids is described. The anticancer activity of the compounds were evaluated in vitro . [ABSTRACT FROM AUTHOR]

The synthesis and characterisation of novel thioacetyl-functionalised terpyridine ligands and their ruthenium and rhodium complexes [Ru(tpy) 2 ](PF 6 ) 2 , [Rh(tpy) 2 ](PF 6 ) 3 , [Ru(phen)(tpy)Cl](PF 6 ), [Rh(phen)(tpy)Cl](PF 6 ) 2 (phen = phenanthroline; tpy = S-[ω-(2,2:6′,2″-terpyridin-4′-yl)phenoxy]alkyl ethanethioate) have been described. Ligands and complexes were characterised by 1 H NMR spectroscopy, mass spectrometry, elemental analysis and cyclic voltammetry data. The crystal structure of the complex [Rh(phen)(tpy)Cl](PF 6 ) 2 (phen = phenanthroline; tpy = 4′-phenyl-2,2′:6′,2″-terpyridine) ( 21 ), have been determined by X-ray crystallography. Complex 21 show a distorted octahedral geometry around the ruthenium centre. Antimicrobial activity toward Escherichia coli at concentrations as low as 5 μM was found for some of the studied complexes. For complexes [Rh(tpy C 6 H 4 O(CH 2 ) 8 SCOCH 3 ) 2 ](PF 6 ) 3 ( 19 ), [Rh(phen)(tpy C 6 H 4 O (CH 2 ) 8 SCOCH 3 )Cl](PF 6 ) 2 ( 31 ) and [Rh(phen)(tpy C 6 H 4 O (CH 2 ) 11 SCOCH 3 )Cl](PF 6 ) 2 ( 32 ), a strong inhibition of in vitro protein synthesis was observed using firefly luciferase. An investigation of cytotoxicity of the complexes against human embryonic kidney cells (HEK293 line) by the MTT assay demonstrates that the toxicity of all tested compounds is of similar magnitude, with IC 50 values of 3–30 μM. [ABSTRACT FROM AUTHOR]

[Display omitted] We report an improved series of ligands targeting prostate specific membrane antigen (PSMA). The new compounds were designed by the introduction of changes in the structure of the aromatic fragment at ε-nitrogen atom of lysine that resulted in improved biological parameters. Some of them demonstrated high selectivity and nanomolar IC 50 values. We synthesized and tested two conjugates with a fluorescent label Sulfo-Cy5 as an example of the use of the obtained PSMA inhibitors as a basis for the creation of diagnostic preparations. [ABSTRACT FROM AUTHOR]

Regioselective synthesis, biological evaluation and 3D-molecular modeling for a series of novel diastereomeric 2-thioxo-5 H -dispiro[imidazolidine-4,3-pyrrolidine-2,3-indole]-2,5(1 H )-diones are described. The studied compounds have been tentatively identified as potent small molecule MDM2/p53 PPI inhibitors and can therefore be reasonably regarded as promising anticancer therapeutics. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most commonly diagnosed men's cancers and remains one of the leading causes of cancer death. The development of approaches to the treatment of this oncological disease is an ongoing process. In this work, we have carried out the selection of ligands for the creation of conjugates based on the drug docetaxel and synthesized a series of three docetaxel conjugates. In vitro cytotoxicity of these molecules was evaluated using the MTT assay. Based on the assay results, we selected the conjugate which showed cytotoxic potential close to unmodified docetaxel. At the same time, the molar solubility of the resulting compound increased up to 20 times in comparison with the drug itself. In vivo evaluation on 22Rv1 (PSMA+) xenograft model demonstrated a good potency of the synthesized conjugate to inhibit tumor growth: the inhibition turned out to be more than 80% at a dose of 30 mg/kg. Pharmacokinetic parameters of conjugate distribution were analyzed. Also, it was found that PSMA-targeted docetaxel conjugate is less toxic than docetaxel itself, the decrease of molar acute toxicity in comparison with free docetaxel was up to 20%. Obtained conjugate PSMA-DOC is a good candidate for further expanded preclinical trials because of high antitumor activity, fewer side toxic effects and better solubility. [Display omitted] • A series of three docetaxel PSMA-targeted conjugates were synthesized. • The most potent conjugate PSMA-DOC demonstrated IC 50 value 2.7 on 22Rv1 cell line. • Tumor growth inhibition on 22Rv1 xenografts was 87% at a PSMA-DOC dosage of 10 mg/kg. • PSMA-DOC conjugate demonstrated increased solubility and decreased general toxicity. • PSMA-DOC pharmacokinetics, subchonic and chronic toxicities were estimated. [ABSTRACT FROM AUTHOR]

• Route for the synthesis of functionalized pyrrolo[1,2- a ]quinoxalines was developed. • The hydrolysis of N -protected furfurylamines produced 1,4-diketones in high yields. • The reductive Paal-Knorr reaction afforded the target pyrrolo[1,2- a ]quinoxalines. • The cytotoxicity of obtained pyrrolo[1,2- a ]quinoxalines was investigated. A method was developed for the synthesis of pyrrolo[1,2- a ]quinoxalines based on an acid-promoted furan ring opening of readily accessible N -(furan-2-ylmethyl)-2-nitroanilines or their heterocyclic analogues followed by a key reductive Paal-Knorr cyclization of the corresponding nitro-1,4-diketones. [ABSTRACT FROM AUTHOR]