32 research outputs found

    Design, Synthesis and Antimicrobial Properties of New Tetracyclic Quinobenzothiazine Derivatives

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    A new method for modifying the structure of tetracyclic quinobenzothiazinium derivatives has been developed, allowing introduction of various substituents at different positions of the benzene ring. The method consists of reacting appropriate aniline derivatives with 5,12-(dimethyl)thioquinantrenediinium bis-chloride. A series of new quinobenzothiazine derivatives was obtained with propyl, allyl, propargyl and benzyl substituents in 9, 10 and 11 positions, respectively. The structure of the obtained compounds was analyzed by 1H and 13C NMR (HSQC, HMBC) and X-ray analysis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212, and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). In addition, all the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. 9-Benzyloxy-5-methyl-12H-quino [3,4-b][1,4]benzothiazinium chloride (6j), 9-propoxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6a) and 9-allyloxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6d) demonstrated high activity against the entire tested microbial spectrum. The activities of the compounds were comparable with oxacillin, tetracycline and ciprofloxacinagainst staphylococcal strains and with rifampicin against both mycobacterial strains. Compound 6j had a significant effect on the inhibition of bacterial respiration as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity, but also bactericidal activity. Preliminary in vitro cytotoxicity screening of the compounds performed using normal human dermal fibroblasts (NHDF) proved that the tested compounds showed an insignificant cytotoxic effect on human cells (IC50 > 37 µM), making these compounds interesting for further investigation. Moreover, the intermolecular similarity of novel compounds was analyzed in the multidimensional space (mDS) of the structure/property-related in silico descriptors by means of principal component analysis (PCA) and hierarchical clustering analysis (HCA), respectively. The distance-oriented structure/property distribution was related with the experimental lipophilic data

    Combination of LIGHT (TNFSF14)-Armed Myxoma Virus Pre-Loaded into ADSCs and Gemcitabine in the Treatment of Experimental Orthotopic Murine Pancreatic Adenocarcinoma

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    Pancreatic ductal adenocarcinoma (PDAC) is a deadly neoplasm. Oncolytic viruses have tumorolytic and immune response-boosting effects and present great potential for PDAC management. We used LIGHT-armed myxoma virus (vMyx-LIGHT) loaded ex vivo into human adipose-derived mesenchymal stem cells (ADSCs) to evaluate murine PDAC treatment in conjunction with gemcitabine (GEM). The cytotoxicity of this treatment was confirmed in vitro using human and murine pancreatic cancer cell cultures, which were more sensitive to the combined approach and largely destroyed. Unlike cancer cells, ADSCs sustain significant viability after infection. The in vivo administration of vMyx-LIGHT-loaded ADSCs and gemcitabine was evaluated using immunocompetent mice with induced orthotopic PDAC lesions. The expression of virus-encoded LIGHT increased the influx of T cells to the tumor site. Shielded virus followed by gemcitabine improved tumor regression and survival. The addition of gemcitabine slightly compromised the adaptive immune response boost obtained with the shielded virus alone, conferring no survival benefit. ADSCs pre-loaded with vMyx-LIGHT allowed the effective transport of the oncolytic construct to PDAC lesions and yielded significant immune response; additional GEM administration failed to improve survival. In view of our results, the delivery of targeted/shielded virus in combination with TGF-β ablation and/or checkpoint inhibitors is a promising option to improve the therapeutic effects of vMyx-LIGHT/ADSCs against PDAC in vivo

    Myxoma virus expressing LIGHT (TNFSF14) pre-loaded into adipose-derived mesenchymal stem cells is effective treatment for murine pancreatic adenocarcinoma

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    Pancreatic ductal adenocarcinoma (PDAC) is a weakly immunogenic fatal neoplasm. Oncolytic viruses with dual anti-cancer properties—oncolytic and immune response-boosting effects—have great potential for PDAC management. Adipose-derived stem cells (ADSCs) of mesenchymal origin were infected ex vivo with recombinant myxoma virus (MYXV), which encodes murine LIGHT, also called tumor necrosis factor ligand superfamily member 14 (TNFSF14). The viability and proliferation of ADSCs were not remarkably decreased (1–2 days) following MYXV infection, in sharp contrast to cells of pancreatic carcinoma lines studied, which were rapidly killed by the infection. Comparison of the intraperitoneal (IP) vs. the intravenous (IV) route of ADSC/MYXV administration revealed more pancreas-targeted distribution of the virus when ADSCs were delivered IP to mice bearing orthotopically injected PDAC. The biodistribution, tumor burden reduction and anti-tumor adaptive immune response were examined. Bioluminescence data, used to assess the presence of the luciferase-tagged virus after IP injection, indicated enhanced trafficking into the pancreata of mice bearing orthotopically-induced PDAC, as compared to tumor-free animals, resulting in extended survival of the treated PDAC-seeded animals and in the boosted expression of key adaptive immune response markers. We conclude that ADSCs pre-loaded with transgene-armed MYXV and administered IP allow for the effective ferrying of the oncolytic virus to sites of PDAC and mediate improved tumor regression

    Towards property profiling: SYNTHESIS and SAR probing of new tetracyclic diazaphenothiazine analogues

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    A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of 1-methyl-3-benzoylthio-4-butylthioquinolinium chloride with 3-aminopyridine derivatives bearing various substituents on the pyridine ring. The direction and mechanism of the cyclization reaction of intermediates with the structure of 1-methyl- 4-(3-pyridyl)aminoquinolinium-3-thiolate was related to the substituents in the 2- and 4-pyridine position. The structures of the compounds were analyzed using 1H, 13C NMR (COSY, HSQC, HMBC) and X-ray analysis, respectively. Moreover, the antiproliferative activity against tumor cells (A549, T47D, SNB-19) and a normal cell line (NHDF) was tested. The antibacterial screening of all the compounds was conducted against the reference and quality control strain Staphylococcus aureus ATCC 29213, three clinical isolates of methicillin-resistant S. aureus (MRSA). In silico computation of the intermolecular similarity was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of structure/property-related descriptors calculated for the novel tetracyclic diazaphenothiazine derivatives. The distance-oriented property evaluation was correlated with the experimental anticancer activities and empirical lipophilicity as well. The quantitative shape-based comparison was conducted using the CoMSA method in order to indicate the potentially valid steric, electronic and lipophilic properties. Finally, the numerical sampling of similarity-related activity landscape (SALI) provided a subtle picture of the SAR trends

    Spectroscopic and crystallographic characterization of a new cathinone derivative: 1‑phenyl‑2‑(butylamino)hexan‑1‑one hydrochloride (N‑butylhexedrone)

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    Purpose In this study, a new cathinone derivative, N-butylhexedrone, emerged on new psychoactive substances (NPS) market in Poland was described and characterized. Methods The compound was analyzed by gas chromatography—mass spectrometry, X-ray crystallography and infrared, Raman, ultraviolet-visible and nuclear magnetic resonance spectroscopic approaches. Results We confirmed the presence of the compound in the seized material and obtained detailed and comprehensive physicochemical characterization of N-butylhexedrone—new cathinone derivative available on the NPS market. Conclusions In this study, we presented chromatographic, spectroscopic and crystallographic characterization of a new cathinone derivative that emerged on the NPS market in 2019. The obtained analytical data should be useful for forensic and toxicological purposes in quick and reliable compound identification

    Potassium ferrate (VI) as the multifunctional agent in the treatment of landfill leachate

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    Possible use of potassium ferrate (VI) (K2FeO4) for the treatment of landfill leachate (pH = 8.9, Chemical Oxygen Demand (COD) 770 mg O2/L, Total Organic Carbon (TOC) 230 mg/L, Total Nitrogen (Total N) 120 mg/L, Total Phosphorus (Total P) 12 mg/L, Total Coli Count (TCC) 6.8 log CFU/mL (Colony-Forming Unit/mL), Most Probable Number (MPN) of fecal enterococci 4.0 log/100 mL, Total Proteolytic Count (TPC) 4.4 log CFU/mL) to remove COD was investigated. Central Composite Design (CCD) and Response Surface Methodology (RSM) were applied for modelling and optimizing the purification process. Conformity of experimental and predicted data (R2 = 0.8477, Radj 2 = 0.7462) were verified using Analysis of Variance (ANOVA). Application of K2FeO4 using CCD/RSM allowed to decrease COD, TOC, Total N, Total P, TCC, MPN of fecal enterococci and TPC by 76.2%, 82.6%, 68.3%, 91.6%, 99.0%, 95.8% and 99.3%, respectively, by using K2FeO4 0.390 g/L, at pH = 2.3 within 25 min. Application of equivalent amount of iron (as FeSO4 7H2O and FeCl3 6H2O) under the same conditions allowed to diminish COD, TOC, Total N, Total P, TCC, MPN of fecal enterococci and TPC only by 38.1%, 37.0%, 20.8%, 95.8%, 94.4%, 58.2%, 90.8% and 41.6%, 45.7%, 29.2%, 95.8%, 92.1%, 58.2%, 90.0%, respectively. Thus, K2FeO4 could be applied as an environmentally friendly reagent for landfill leachate treatment

    Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses

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    Progress in genetic engineering led to the emergence of some viruses as potent anticancer therapeutics. These oncolytic viruses combine self-amplification with dual antitumor action: oncolytic (destruction of cancer cells) and immunostimulatory (eliciting acquired antitumor response against cancer epitopes). As any other viruses, they trigger antiviral response upon systemic administration. Mesenchymal stem cells are immature cells capable of self-renewing and differentiating into many cell types that belong to three germinal layers. Due to their inherent tumor tropism mesenchymal stem cells loaded with oncolytic virus can improve delivery of the therapeutic cargo to cancer sites. Shielding of oncolytic viral construct from antiviral host immune response makes these cells prospective delivery vehicles to even hard-to-reach metastatic neoplastic foci. Use of mesenchymal stem cells has been criticized by some investigators as limiting proliferative abilities of primary cells and increasing the risk of malignant transformation, as well as attenuating therapeutic responses. However, majority of preclinical studies indicate safety and efficacy of mesenchymal stem cells used as carriers of oncolytic viruses. In view of contradictory postulates, the debate continues. The review discusses mesenchymal stem cells as carriers for delivery of genetically engineered oncolytic constructs and focuses on systemic approach to oncoviral treatment of some deadly neoplasms

    Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma

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    Oncolytic viruses can target neoplasms, triggering oncolytic and immune effects. Their delivery to melanoma lesions remains challenging. Bone-marrow-derived mesenchymal stem cells (MSCs) were shown to be permissive for oncolytic myxoma virus (MYXV), allowing its transfer to melanoma cells, leading to their killing. Involvement of progeny virus was demonstrated in the transfer from MSCs to co-cultured melanoma cells. The inhibitory effect of virus on melanoma foci formation in murine lungs was revealed using melanoma cells previously co-cultured with MYXV-infected MSCs. Virus accumulation and persistence in lungs of lesion-bearing mice were shown following intravenous administration of MSC-shielded MYXV construct encoding luciferase. Therapy of experimentally induced lung melanoma in mice with interleukin (IL)-15-carrying MYXV construct delivered by MSCs led to marked regression of lesions and could increase survival. Elevated natural killer (NK) cell percentages in blood indicated robust innate responses against unshielded virus only. Lung infiltration by NK cells was followed by inflow of CD8+ T lymphocytes into melanoma lesions. Elevated expression of genes involved in adaptive immune response following oncolytic treatment was confirmed using RT-qPCR. No adverse pathological effects related to MSC-mediated oncolytic therapy with MYXV were observed. MSCs allow for safe and efficient ferrying of therapeutic MYXV to pulmonary melanoma foci triggering immune effects

    Crystal structures and other properties of ephedrone (methcathinone) hydrochloride, N‑acetylephedrine and N‑acetylephedrone

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    Purpose Three compounds obtained from ephedrine were identified and characterized by various instrumental analytical methods. Ephedrone (methcathinone) hydrochloride and its fundamental derivatives N-acetylephedrine and N-acetylephedrone were analyzed as precursors of a cathinone derivative. Methods The obtained samples were analyzed by gas chromatography coupled with mass spectrometry, nuclear magnetic resonance spectroscopy, infrared and Raman spectroscopy, and X-ray crystallography. Results The three compounds were confirmed as: N-methyl-2-amino-1-phenylpropan-1-one (methcathinone) hydrochloride, N-acetyl-N-methyl-2-amino-1-phenylpropan-1-one (cathinone derivative), and N-acetyl-N-methyl-2-amino-1-phenylpropan- 1-ol (acetyl derivative of ephedrine). Conclusions X-ray crystallography is especially useful for identifying the new designer drugs and their different precursor forms
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