Preparation of fluorinated carbocyclic derivatives of nucleosides as potential viral replication inhibitors

This master thesis is dedicated to the preparation of fluorinated derivatives of carbocyclic nucleosides, that may serve as flaviviral replication inhibitors. Preparation of both monofluorinated as well as gem-difluorinated analogs of ribo and 2'-deoxyribonucleoside was attempted. While a suitable and reliable route for the preparation of monofluorinated compounds way found, synthesis of gem-difluorinated turned out to be rather challenging. Although most of the presented work dealt with compounds bearing adenine as a nucleobase, the universal applicability of the developed procedures, demonstrated on the preparation of a guanosine-type molecule, suggests that after slight optimization larger series of this type of compounds could be prepared

Synthesis of novel prodrugs for antiviral therapy

This bachelor thesis is dedicated to preparation of prodrugs derived from 2'-C- methyladenosine, which is a potent inhibitor of the RNA dependent RNA polymerase of flaviviruses. Prodrugs modifying 3' and 5' hydroxy groups able to deliver the drug to brain and were prepared. As targeting moieties tropine and the redox system trigonelline/1,4- dihydrotrigonelline were used. In the case of tropine a suitable method for the preparation of prodrugs was developed. Reliable procedure for performing the last step of synthesis of compounds utilizing the trigonelline redox system is yet to be discovered

Preparation of fluorinated carbocyclic derivatives of nucleosides as potential viral replication inhibitors

This master thesis is dedicated to the preparation of fluorinated derivatives of carbocyclic nucleosides, that may serve as flaviviral replication inhibitors. Preparation of both monofluorinated as well as gem-difluorinated analogs of ribo and 2'-deoxyribonucleoside was attempted. While a suitable and reliable route for the preparation of monofluorinated compounds way found, synthesis of gem-difluorinated turned out to be rather challenging. Although most of the presented work dealt with compounds bearing adenine as a nucleobase, the universal applicability of the developed procedures, demonstrated on the preparation of a guanosine-type molecule, suggests that after slight optimization larger series of this type of compounds could be prepared.Tato diplomová práce se zabývá přípravou fluorovaných derivátů karbocyklických nukleosidů, které by mohly sloužit jako inhibitory replikace flavivrů. Byly připravovány monofluorované i gem-difluorované analogy ribo i 2'-deoxyribonukleosidů. Zatímco pro přípravu monofluorovaných sloučenin byly nalezeny vhodné a poměrně spolehlivé syntetické cesty, syntéza gem-difluorovaných látek se ukázala jako velmi komplikovaná. Ačkoli se většina syntéz prezentovaných v této práci zabývala přípravou látek s adeninem jakožto nukleobazí, obecná aplikovatelnost vyvinutých postupů byla demonstrována přípravou molekuly guanosinového typu. Po optimalizaci by tedy mělo být možné uvedené reakční sekvence využít k přípravě rozsáhlejších sérií látek.Katedra organické chemieDepartment of Organic ChemistryPřírodovědecká fakultaFaculty of Scienc

Návrh řešení transportu dílců na pracoviště oprav kontaminovaných dílů JE VVER 440 v prostoru haly JE závodu 6, k.p. VŽSKG

Prezenční345 - Katedra mechanické technologieNeuveden

Use of 5-Carboxymethyl3-Mercapto-1,2,4-Triazino-[5,6-B]Indoles and their pharmaceutical composition

: The present invention relates to the use of 5-carboxymethyl-3- mercapto-1,2,4-triazino-[5,6-b]indoles (the general formula (I)) and their pharmaceutically acceptable salts hydrates and solvates thereof for the use in treatment, control and prevention of human and veterinary diseases in which activities of aldo- keto reductases AKR1B1 and AKR1B10 are key etiological factors for their development and progress such as the development of diabetic complications (macro-, microangiopathy, atherosclerosis, retinopathy, cataracts, nephropathy, neuropathy, bone mass loss and atherosclerosis), inflammatory diseases (uveitis, sepsis, periodontitis, asthma and colorectal cancer), abnormal proliferation of vascular smooth muscle cells in atherosclerosis and restenosis, lung carcinoma in smokers, and several types of cancer (lung, breast, hepatic, prostate, pancreatic, endometrial cancer, cervical cancer, and cervical adenocarcinoma), diseases of the female reproductive system (menstrual disorders and fertility problems), timing of parturition, mood disorders, psychiatric and neurological diseases. The present invention relates to pharmaceutical compositions comprising effective amount of 5-carboxymethyl-3-mercapto-1,2,4-triazino-[5,6-b]indoles of the general formula (I) and a pharmaceutically acceptable carrier for the use in treatment, control and prevention of human and veterinary diseases. (Formula (I))Peer reviewedÚstav Experimentálnej Farmakilógie a Toxikológie Sav, Consejo Superior de Investigaciones Científicas, Centrum vedecko-technických informácií SRA1 Solicitud de adición a la patent

Novel hexahydropyridoindole derivative as prospective agent against oxidative damage in pancreatic β cells

The potential protective effect of (±)-8-methoxy-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester (II) was assessed against hydrogen peroxide (H2O2)-cytotoxicity in rat pancreatic INS-1E β cells and compared with the effect of the related pyridoindole, stobadine (I), a promising indole-type reference antioxidant. Only pre-treatment with the compound (II) led to a significant preservation of the metabolic and secretory functions of the cells exposed to H2O2. The caspase-9 and -3 activities, as well as the early apoptotic changes of plasma membrane, were suppressed in the cells pre-incubated with both of compounds tested. However, only pyridoindole (II) inhibited profoundly the time-delayed apoptotic changes, These results suggest that pyridoindole (II) characterized by enhanced intrinsic antioxidant efficiency, may protect β cells against cytotoxic effects of H2O2, involved in the development of both type 1 and type 2 diabetes

Selectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase

Novel oxotriazinoindoles (OTIs) were recently reported as highly efficient and selective aldose reductase inhibitors. Here, a series of novel N(2)-substituted oxotriazinoindoles was developed with the aim to investigate molecular interactions within the aldose reductase (ALR2) inhibitor binding site. About twice increased inhibition efficacy of the most efficient derivative 14 (N(2)-CH2CH2COOH) compared to the unsubstituted lead OTI was obtained, yet at the expense of selectivity relative to anti-target aldehyde reductase (ALR1). To explain the major drop in selectivity, observed also in other N(2)-substituted derivatives, in silico molecular modeling approach revealed the role of extra interactions with the residues of Arg309, Arg312 and Met302 located in the additional C-terminal loop of ALR1 missing in ALR2, which can prevent or enhance binding in ALR1. These key findings will be used for development of the next generation of selective OTI inhibitors. (Figure presented.)

General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

Cemtirestat, 3-mercapto-5H-[1,2,4]-triazino[5,6-b]indole-5-acetic acid was recently designed and patented as a highly selective and efficient aldose reductase inhibitor endowed with antioxidant activity. The aim of the present study was to assess the general toxicity of cemtirestat using in silico predictions, in vitro and in vivo assays. ProTox-II toxicity prediction software gave 17 “Inactive” outputs, a mild hepatotoxicity score (0.52 probability) along with a predicted LD50 of 1000 mg/kg. Five different cell lines were used including the immortalized mouse microglia BV-2, the primary human fibroblasts VH10, the insulinoma pancreatic β-cells INS-1E, the human colon cancer cells HCT116 and the human immortalized epithelial endometrial cell lines HIEEC. In contrast to the clinically used epalrestat, cemtirestat showed remarkably low cytotoxicity in several different cell culture viability tests such as MTT proliferation assay, neutral red uptake, BrdU incorporation, WST-1 proliferation assay and propidium iodide staining followed by flow cytometry. In a yeast spotting assay, the presence of cemtirestat in incubation of Saccaromyces cerevisiae at concentrations as high as 1000 µM did not affect cell growth rate significantly. In the 120-day repeated oral toxicity study in male Wistar rats with daily cemtirestat dose of 6.4 mg/kg, no significant behavioral alterations or toxicological manifestations were observed in clinical and pathological examinations or in hematological parameters. In summary, these results suggest that cemtirestat is a safe drug that can proceed beyond preclinical studies