Аналіз застосовності комерційно доступного хімічного простору для використання у 19F ЯМР FAXS методі на прикладі НВП «Єнамін»

Aim. To analyze commercially available fluorine containing compounds for the possibility of their use in the 19F NMR FAXS method.Materials and methods. The selection of fluorine-containing fragments for the study was performed using 3.9 million instock screening compounds and 248,000 in-stock building-blocks from Enamine Ltd library. The selection and classification of the compounds was carried out using the DataWarrior and KNIME software. The Fluorinated Fragments library of Enamine Ltd. containing 6377 compounds, was also analyzed. To analyze the abovementioned sets of substances, the multistep workflows specially designed were used.Results and discussion. As a result of applying the workflow developed to the compound sets (both screening compounds and building blocks), 13 800 compounds were selected and further classified according to the presence of one out of 12 fluorine-containing groups. The Fluorinated Fragments library was also subjected to a similar workflow. For the latter, 8 out of 12 fluorine-containing groups were identified. Additionally, experimental 19F NMR chemical shift values for Fluorinated Fragments library compounds spectra were analyzed. It has been found that some structural classes have areas of chemical shifts intersection. On the other hand, the ranges from –40 to –60 ppm and beyond –160 ppm are free from any group of compounds from the library analyzed.Conclusions. The analysis has shown that commercially available fluorine-containing fragments do not satisfy the needs of the 19F NMR FAXS method, and further expansion of the chemical space of fluorine-containing compounds by increasing their diversity is required.Мета. Проаналізувати комерційно доступні флуоровмісні сполуки на можливість їх застосування в конкурентному скринінгу за допомогою 19F ЯМР FAXS методу.Матеріали та методи. Відбір флуоровмісних фрагментів для дослідження проводили з використанням наявних на складі компанії ТОВ «НВП «Єнамін» 3,9 млн скринінгових сполук та 248000 будівельних блоків. Відбір та розподіл сполук по групах виконували за допомогою програм DataWarrior та KNIME. Проаналізували бібліотеку флуорованих фрагментів ТОВ «НВП «Єнамін», що містить 6377 сполук. Для аналізу вищезазначених наборів речовин використовували спеціально розроблені багатоступеневі алгоритми.Результати та їх обговорення. У результаті застосування розробленого алгоритму до скринінгових сполук та будівельних блоків відібрано 13800 представників, які додатково класифіковано за наявністю однієї з 12 флуоровмісних груп. Бібліотеку флуорованих фрагментів також піддано подібній процедурі. Для останньої групи досліджуваних сполук ідентифіковано наявність 8 з 12 флуоровмісних фрагментів. Крім того, проаналізовано експериментальні значення хімічного зсуву, отримані із 19F ЯМР спектрів бібліотеки флуорованих фрагментів. З’ясовано, що деякі структурні класи мають зони перетину хімічних зсувів. З іншого боку, у діапазонах від –40 до –60 м.д. і більше –160 м.д. не представлено жодної сполуки з аналізованої бібліотеки.Висновки. Аналіз засвідчив, що наявні комерційно доступні флуоровмісні фрагменти не задовольняють потреби 19F NMR FAXS методу, а тому необхідно розширювати хімічний простір флуоровмісних сполук шляхом збільшення їх різноманіття

Mast cells in peritoneal fluid in rats with experimentally induced peritoneal adhesions.

Mast cells (MC) produce, store and release many biologically active substances, especially inflammatory factors, chemotactic substances for neutrophiles, cytokines and prostaglandins. They play very important role in fibrinosis and they are an important factor in peritoneal adhesions formation and lysis. In this study we tried to evaluate role of mast cells in peritoneal adhesions formation. We estimated number of mast cells in peritoneal fluid in rats with experimentally developed peritoneal adhesions. The number of mast cells per ml was counted in flow cytometry in specimens of peritoneal fluid taken from operated rats. The fluid was taken in standardized conditions the same for each group at the first operation and during reoperation. Peritoneal cavity was washed with 0.9% Saline solution. MC were visualized using indirect immunohistochemical method LSAB with mouse antibody. The animals were divided into 4 groups. 1 st group was control group (n=20) on which the abdomen was opened and closed without any manipulations, and the reoperation was done after 72 hours. The other groups (2, 3, 4; n=20 for each group) were operated and scarification of the partial peritoneum and serosa was performed. The rats were brought back to conscious and then were reoperated respectively after 24, 72 and 168 hours after first surgery. After the laparotomy and damage of the peritoneum we observed formation of the peritoneal adhesions between intestine loops and between intestines and damaged parietal peritoneum. Also the higher number of mast cells was observed in the groups of animals with damaged peritoneum. The highest number of peritoneal adhesions was observed in the group of animals reoperated after 72 hours. After 72 and 168 hours the higher number of MC and neutrophils was observed. The difference was statistically significant. The percentage of mast cells was increasing during the experiment duration. It was different from other cells populations which decreased after 168 hours. The MC and neutrophils were cell population which changed significantly after manipulations in peritoneal cavity. It is very probable that they play an important role in peritoneal adhesions formation

Гетероциклізація або реакції каплінгу: випадок ДНК-кодованих бібліотек

Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox. DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-weight antibodies and peptides on the other hand. On its natural path to overcoming the “childhood diseases” typical for every novel technology, DELT has reached a point where the chemical diversity of DNA-encoded libraries (DELs) becomes an important factor to look out for. In this paper, we aim to take a closer look at the chemical diversity of DELs in their present state and find the ways to improve it.Results and discussion. We have identified the DEL-viable building blocks from the Enamine Ltd. stock collection, as well as from Chemspace Ltd. virtual collection, using the SMARTS set, which takes into account all the necessary structural restrictions. Using modern cheminformatics tools, such as Synt-On, we have analyzed the scaffold diversity of both stock and virtual core bi- and tri-functional building blocks (BBs) suitable for DNA-tolerant reactions. The identification of scaffolds from the most recently published on-DNA heterocyclization reactions and analysis of their inclusion into the existing BBs space have shown that novel DNA-tolerant heterocyclizations are extremely useful for expanding chemical diversity in DEL technologies.Conclusions. The analysis performed allowed us to recognize which functional groups should be prioritized as the most impactful when the new BBs are designed. It is also made clear that the development of new DNA-tolerant reactions, including heterocyclizations, have a significant potential to further expand DEL molecular diversity.Мета. Технології ДНК-кодованих бібліотек (DELT) поступово стають важливою частиною стандартного набору інструментів для пошуку нових лікарських субстанцій. Наразі DELT прагне знайти своє місце у просторі між класичними низькомолекулярними кандидатами у ліки з одного боку та високомолекулярними антитілами й пептидами з іншого. На своєму шляху до подолання «дитячих хвороб», характерних для кожної нової технології, DELT досягли того моменту, коли хімічна різноманітність ДНК-кодованих бібліотек (DEL) стає важливим фактором, на який варто звернути увагу. У цій статті ми прагнемо ближче розглянути хімічне різноманіття ДНК-кодованих бібліотек у їхньому поточному стані та знайти можливості для його покращення.Результати та їх обговорення. Ми визначили DEL-життєздатні будівельні блоки з наявної колекції Enamine Ltd., а також із віртуальної колекції Chemspace Ltd., використовуючи набір SMARTS, який враховує всі необхідні структурні обмеження. За допомогою таких сучасних інструментів хемоінформатики, як Synt-On, ми проаналізували різноманітність каркасів як уже синтезованих, так і віртуальних бі- та трифункціональних білдинг-блоків (BB), придатних для реакцій, у яких ДНК залишається інтактною. Ідентифікація молекулярних скафолдів, використовуваних у нещодавно опублікованих «on-DNA» реакціях гетероциклізації, та аналіз їх внесення до простору BB, який існує, засвідчили, що нові толерантні до ДНК гетероциклізації є надзвичайно корисними для розширення хімічної різноманітності в технологіях DEL.Висновки. Виконаний аналіз дозволив нам визначити, яким функціональним групам варто віддати пріоритет як найбільш впливовим у процесі дизайну нових BB. Також стало зрозуміло, що розвиток нових толерантних до ДНК реакцій, включаючи гетероциклізації, має значний потенціал для подальшого розширення молекулярного різноманіття DEL

Influence of Y2O3 and Fe2Y additions on the formation of nano-scale oxide particles and the mechanical properties of an ODS RAF steel

The main goal of this work was to manufacture an oxide dispersion strengthened (ODS) reduced activation ferritic steel from a pre-alloyed, gas atomised Fe-14Cr-2W-0.2Ti (in wt.%) powder mechanically alloyed with either 0.3%Y2O(3) or 0.5%Fe2Y particles and consolidated by hot isostatic pressing, and to investigate its microstructure, microhardness and Charpy impact properties

Mast cells in peritoneal fluid in rats with experimentally induced peritoneal adhesions.

Mast cells (MC) produce, store and release many biologically active substances, especially inflammatory factors, chemotactic substances for neutrophiles, cytokines and prostaglandins. They play very important role in fibrinosis and they are an important factor in peritoneal adhesions formation and lysis. In this study we tried to evaluate role of mast cells in peritoneal adhesions formation. We estimated number of mast cells in peritoneal fluid in rats with experimentally developed peritoneal adhesions. The number of mast cells per ml was counted in flow cytometry in specimens of peritoneal fluid taken from operated rats. The fluid was taken in standardized conditions the same for each group at the first operation and during reoperation. Peritoneal cavity was washed with 0.9% Saline solution. MC were visualized using indirect immunohistochemical method LSAB with mouse antibody. The animals were divided into 4 groups. 1 st group was control group (n=20) on which the abdomen was opened and closed without any manipulations, and the reoperation was done after 72 hours. The other groups (2, 3, 4; n=20 for each group) were operated and scarification of the partial peritoneum and serosa was performed. The rats were brought back to conscious and then were reoperated respectively after 24, 72 and 168 hours after first surgery. After the laparotomy and damage of the peritoneum we observed formation of the peritoneal adhesions between intestine loops and between intestines and damaged parietal peritoneum. Also the higher number of mast cells was observed in the groups of animals with damaged peritoneum. The highest number of peritoneal adhesions was observed in the group of animals reoperated after 72 hours. After 72 and 168 hours the higher number of MC and neutrophils was observed. The difference was statistically significant. The percentage of mast cells was increasing during the experiment duration. It was different from other cells populations which decreased after 168 hours. The MC and neutrophils were cell population which changed significantly after manipulations in peritoneal cavity. It is very probable that they play an important role in peritoneal adhesions formation

Microstructure and mechanical properties of an ODS RAF steel fabricated by hot extrusion or hot isostatic pressing

Ingots of an oxide dispersion strengthened reduced activation ferritic steel with the Fe-14Cr-2W-0.3Ti-0.3Y(2)O(3) chemical composition (in wt.%) were synthesized by mechanical alloying of elemental powders with 0.3 wt.% Y2O3 particles in a planetary ball mill, in a hydrogen atmosphere. and compacted by either hot extrusion or hot isostatic pressing. The microstructures of the obtained materials were characterized by means of light microscopy, transmission electron microscopy and chemical analyses. The mechanical properties were evaluated by means of Vickers microhardness measurements and tensile tests. It was found that the microstructure of both materials is composed of ferritic grains having a submicron size and containing nanometric Y-Ti-O oxide particles with a mean size of about 10 nm, uniformly distributed in the matrix. The oxide particles in the hot extruded steel were identified as YTiO3 phase. In larger (>10 nm) oxide particles Cr was found next to Ti, Y and O. The steel produced by hot extrusion exhibits much higher tensile strength and hardness at low to moderate temperatures, as compared to the steel fabricated by hot isostatic pressing, which was mainly attributed to smaller pores but also to more severe work hardening in the case of the hot extruded steel. (C) 2011 Elsevier B.V. All rights reserved

Review on the EFDA work programme on nano-structured ODS RAF steels

This proceeding is: The 14th International Conference on Fusion Reactor Materials (ICFRM-14) was held at the Sapporo Convention Center in Sapporo, Japan from 7 to 12 September 2009.The 2008─2009 work programme of the European research project on nano-structured oxide dispersion strengthened (ODS) reduced activation ferritic (RAF) steels is being organized along the four following programmatic lines: (1) improve the present generation of nano-structured ODS RAF steels; (2) start the industrial fabrication of the present generation of nano-structured ODS RAF steels; (3) develop an optimised generation of nano-structured and nano-grained ODS RAF steels; (4) investigate the stability of present and optimised generation of nano-structured ODS RAF steels under creep and irradiation. This paper presents the main objectives of current R&D activities being performed within the European research project on nano-structured ODS RAF steels, the main obtained results and the main future activities in the case of the four programmatic lines mentioned just above.This work, supported by the European Communities, was carried out within the framework of the European Fusion Development Agreement.Publicad

Effect of HAP decomposition on the corrosion behavior of Ti-HAP biocomposites

Ti-HAP biocomposites are gained attention for combining the attractive properties of Ti and hydroxyapatite (HAP). However, the decomposition of HAP at elevated processing temperatures is a major concern since it can lead to structural flaws and may deteriorate the corrosion resistance of Ti. The present study aims to investigate the corrosion behavior of Ti-HAP composite processed by powder metallurgy by performing potentiodynamic polarization and electrochemical impedance spectroscopy in 0.9wt% NaCl solution at body temperature. Results show that the presence of Ti lowers the HAP decomposition temperatures resulting in the formation of HAP-depleted zones acting as electrochemically active sites, decreasing the corrosion resistance.This study was supported by the Foundation for Science andTechnology (FCT), Portugal with the reference projects UID/EEA/04436/2013, EXCL/EMS-TEC/0460/2012, and M-ERA-NET/0001/2015, as well, by FEDER funds through the COMPETE 2020–Programa Operacional Competitividade eInternacionalização (POCI) with the reference project POCI-01-0145-FEDER-006941. The authors would also like toacknowledge Prof. Ana Senos (University of Aveiro) andProf. José Carlos Teixeira (University of Minho) for theprovision of the characterization facilities