Selective synthesis of A-ring Е-arylidene derivatives from ß-sitosterol and their activity.

A series of 24-ethylcholest-4-ene-3,6-dione 2E-arylidene-derivatives has been synthesized by a Claisen-Schmidt reaction from a natural phytosterol ß-sitosterol with yields of 80-85%. The structure of the obtained compounds was confirmed by NMR spectroscopy, including two-dimensional correlation experiments. The synthesized compounds were evaluated for their in vitro cytotoxicity and α-glucosidase inhibitory activity. It was established that compound 3 with pyridin-3-ylmethylene moiety exhibited a selective cytotoxic effect against the U251 cancer cell line with 99.31% inhibition of cancer cell growth. Compounds with pyridin-4-ylmethylene 4 and furan-2-ylmethylene-5 fragments were the most active inhibitors of α-glucosidase with IC50 64.00 and 38.95 µM, being 3- and 5-times more active than acarbose. Binding mode to α-glucosidase and ADMET characteristics for the lead molecule 5 were proposed computationally. To sum up, an efficient approach to the derivatives with promising antidiabetic activity based on available natural product ß-sitosterol is suggested.

Mutation Effect of Ionizing and Non-Ionizing Electromagnetic Radiation on Drosophila melanogaster.

The frequency of D. melanogaster embryonic death was estimated using the method of dominant lethal mutations after exposure to ionizing γ-radiation and non-ionizing pulsed magnetic field. γ-Radiation had a dose-dependent mutational effect on D. melanogaster. A pronounced increase in embryonic death was observed starting from a dose of 3 Gy and reaches a plateau at 60 Gy due to the maximum death of eggs. When D. melanogaster was exposed to pulsed magnetic field, the effect did not depend on the exposure time; a statistically significant genotoxic effect was detected after 5-h exposure.

Synthesis of C17-[5-methyl-1,3]-oxazoles by N-propargylation of triterpenic acids and evaluation of their cytotoxic activity.

A series of unexpected triterpenic C17-[5-methyl-1,3]-oxazoles along with targeted N-propargylamides was synthesized by an interaction of acid chlorides with propargylamine hydrochloride. We proposed that the formation of methyl oxazole passes through an alternative pathway by the participation of the terminal alkyne carbon atom and acid chloride intermediate with following intramolecular rearrangements. The synthesized compounds were evaluated for their cytotoxicity at the U.S. National Cancer Institute. 28-Nor-17-(5-methyloxazol-2-yl)-2-cyano-2,4-seco-3-nor-lup-4(23),20(29)-diene has demonstrated the highest activity with GI50 ranged from 1.03 to 16.4 µM against different cancer cell lines. Molecular docking in Kelch domain of Keap1 protein was performed to study a possible molecular target. Thus, we have shown for the first time that triterpenic C17-[5-methyl-1,3]-oxazoles are alternative products of the interaction of triterpenic acid chlorides with propargylamine hydrochloride and they have an advantage over corresponding N-propargylamides as cytotoxic agents.

The influenza A virus NS genome segment displays lineage-specific patterns in predicted RNA secondary structure.

BACKGROUND: Influenza A virus (IAV) is a segmented negative-sense RNA virus that causes seasonal epidemics and periodic pandemics in humans. Two regions (nucleotide positions 82-148 and 497-564) in the positive-sense RNA of the NS segment fold into a multi-branch loop or hairpin structures. RESULTS: We studied 25,384 NS segment positive-sense RNA unique sequences of human and non-human IAVs in order to predict secondary RNA structures of the 82-148 and 497-564 regions using RNAfold software, and determined their host- and lineage-specific distributions. Hairpins prevailed in avian and avian-origin human IAVs, including H1N1pdm1918 and H5N1. In human and swine IAV hairpins distribution varied between evolutionary lineages. CONCLUSIONS: These results suggest a possible functional role for these RNA secondary structures and the need for experimental evaluation of these structures in the influenza life cycle.

Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer.

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

[Conservation of the MC domains in eukaryotic termination factor eRF3].

Eukaryotic translation termination employs two protein factors, eRF1 and eRF3. Proteins of the eRF3 family each consist of three domains. The N and M domains vary in different species, while the C domains are highly homologous. The MC domains of Homo sapiens eRF3a (hGSPT I), Xenopus laevis eRF3 (XSup35), and Mus musculus eRF3a (mGSPTI) and eRF3b (mGSPT2) were found to compensate for the sup35-21(ts) temperature-sensitive mutation and lethal disruption of the SUP35 gene in yeast Saccharomyces cerevisiae. At the same time, strains containing the MC domains of the eRF3 proteins from different species differed in growth rate and the efficiency of translation termination.

[Influence of cultivation conditions on the expression of Yersinia pestis YopE].

With the use three types of nutrient media made it possible to study the specific features of the biosynthesis of YopE, one of the main effector proteins, coded by Yersinia pestis virulence plasmid. This protein was proved to be produced practically at all stages of Y. pestis parasitism in the host body. The above-mentioned antigen was found capable of being synthesized, depending on the conditions of Y. pestis cultivation, in the form of membrane-linked (extracellularly and under phagosomal conditions) or secreted substance, mainly in phagolysosome. In the latter case the maximum level of its expression was registered. The experimental confirmation of YopE localization in the form of superficially localized antigen/receptor at the period of the extracellular growth of bacteria is presented, which suggests its important role in the realization of the virulent properties of Y. pestis and, together with the known data on the protective properties of the antigen, indicates the prospects of its use as the basis for the creation of new chemical antiplague vaccine.