17(E)-Picolinylidene androstane derivatives as potential inhibitors of prostate cancer cell growth: Antiproliferative activity and molecular docking studies

We report a rapid and efficient synthesis of A-ring modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives from dehydroepiandrosterone. Compounds were validated spectroscopically and structurally characterized by X-ray crystallography. Virtual screening by molecular docking against clinical targets of steroidal anticancer drugs (ERα, AR, Aromatase and CYP17A1) suggests that 17(E)-picolinylidene, but not 17α-picolyl androstanes could specifically interact with CYP17A1 (17α-hydroxylase) with similar geometry and affinity as Abiraterone, a 17-pyridinyl androstane drug clinically used in the treatment of prostate cancer. In addition, several 17(E)-picolinylidene androstanes demonstrated selective antiproliferative activity against PC3 prostate cancer cells, which correlates with Abiraterone antiproliferative activity and predicted CYP17A1 binding affinities. Based on these preliminary results, 17(E)-picolinylidene androstane derivatives could be a promising starting point for the development of new compounds for the treatment of prostate cancer.     

Bioinformatics analysis of disordered proteins in prokaryotes

Background  

A significant number of proteins have been shown to be intrinsically disordered, meaning that they lack a fixed 3 D structure or contain regions that do not posses a well defined 3 D structure. It has also been proven that a protein's disorder content is related to its function. We have performed an exhaustive analysis and comparison of the disorder content of proteins from prokaryotic organisms (i.e., superkingdoms Archaea and Bacteria) with respect to functional categories they belong to, i.e., Clusters of Orthologous Groups of proteins (COGs) and groups of COGs-Cellular processes (Cp), Information storage and processing (Isp), Metabolism (Me) and Poorly characterized (Pc).     

Dramatic differences in the roles in lipid metabolism of two isoforms of diacylglycerol kinase

Lipid species changes for SV40-transformed fibroblasts from wild-type or from diacylglycerol kinase-epsilon (DGKepsilon) or diacylglycerol kinase-alpha (DGKalpha) knockout mice were determined for glycerophospholipids, polyphosphatidylinositides (GPInsP n ) and diacylglycerol (DAG) using direct infusion mass spectrometry. Dramatic differences in arachidonate (20:4 fatty acid)-containing lipids were observed for multiple classes of glycerophospholipids and polyphosphatidylinositides between wild-type and DGKepsilon knockout cells. However, no difference was observed in either the amount or the acyl chain composition of DAG between DGKepsilon knockout and wild-type cells, suggesting that DGKepsilon catalyzed the phosphorylation of a minor fraction of the DAG in these cells. The differences in arachidonate content between the two cell lines were greatest for the GPInsP n lipids and lowest for DAG. These findings indicate that DGKepsilon plays a significant role in determining the enrichment of GPInsP n with 20:4 and that there is a pathway for the selective translocation of arachidonoyl phosphatidic acid from the plasma membrane to the endoplasmic reticulum. In contrast, no substantial difference was observed in the acyl chain composition of any class of glycerophospholipid or diacylglycerol between lipid extracts from fibroblasts from wild-type mice or from DGKalpha knockout mice. However, the cells from the DGKalpha knockout mice had a higher concentration of DAG, consistent with the lack of downregulation of the major fraction of DAG by DGKalpha, in contrast with DGKepsilon that is primarily responsible for enrichment of GPInsP n with arachidonoyl acyl chains.     

Cytotoxic and Antimicrobial Activity of Dehydrozingerone based Cyclopropyl Derivatives

A small series of 1‐acetyl‐2‐(4‐alkoxy‐3‐methoxyphenyl)cyclopropanes was prepared, starting from dehydrozingerone (4‐(4‐hydroxy‐3‐methoxyphenyl)‐3‐buten‐2‐one) and its O‐alkyl derivatives. Their microbiological activities toward some strains of bacteria and fungi were tested, as well as their in vitro cytotoxic activity against some cancer cell lines (HeLa, LS174 and A549). All synthesized compounds showed significant antimicrobial activity and expressed cytotoxic activity against tested carcinoma cell lines, but they showed no significant influence on normal cell line (MRC5). Butyl derivative is the most active on HeLa cells (IC₅₀ = 8.63 μm ), while benzyl one is active against LS174 and A549 cell lines (IC₅₀ = 10.17 and 12.15 μm , respectively).     

In vitro assessment of the growth and plasma membrane H+‐ATPase inhibitory activity of ebselen and structurally related selenium‐ and sulfur‐containing compounds in Candida albicans

Ebselen (EB, compound 1) is an investigational organoselenium compound that reduces fungal growth, in part, through inhibition of the fungal plasma membrane H⁺‐ATPase (Pma1p). In the present study, the growth inhibitory activity of EB and of five structural analogs was assessed in a fluconazole (FLU)‐resistant strain of Candida albicans (S2). While none of the compounds were more effective than EB at inhibiting fungal growth (IC₅₀ ～ 18 μM), two compounds, compounds 5 and 6, were similar in potency. Medium acidification assays performed with S2 yeast cells revealed that compounds 4 and 6, but not compounds 2, 3, or 5, exerted an inhibitory activity comparable to EB (IC₅₀ ～ 14 μM). Using a partially purified Pma1p preparation obtained from S2 yeast cells, EB and all the analogs demonstrated a similar inhibitory activity. Taken together, these results indicate that EB analogs are worth exploring further for use as growth inhibitors of FLU‐resistant fungi.     

The FANCM ortholog Fml1 promotes recombination at stalled replication forks and limits crossing over during DNA double-strand break repair

The Fanconi anemia (FA) core complex promotes the tolerance/repair of DNA damage at stalled replication forks by catalyzing the monoubiquitination of FANCD2 and FANCI. Intriguingly, the core complex component FANCM also catalyzes branch migration of model Holliday junctions and replication forks in vitro. Here we have characterized the ortholog of FANCM in fission yeast Fml1 in order to understand the physiological significance of this activity. We show that Fml1 has at least two roles in homologous recombination-it promotes Rad51-dependent gene conversion at stalled/blocked replication forks and limits crossing over during mitotic double-strand break repair. In vitro Fml1 catalyzes both replication fork reversal and D loop disruption, indicating possible mechanisms by which it can fulfill its pro- and antirecombinogenic roles.     

The effects of hemicelluloses and lignin removal on water uptake behavior of hemp fibers

This study investigated the individual influences of hemicelluloses and lignin removal on the water uptake behavior of hemp fibers. Hemp fibers with different content of either hemicelluloses or lignin were obtained by chemical treatment with 17.5% sodium hydroxide or 0.7% sodium chlorite. Various tests (capillary rise method, moisture sorption, water retention power) were applied to evaluate the change in water uptake of modified hemp fibers. The obtained results show that when the content of either hemicelluloses or lignin is reduced progressively by chemical treatment, the capillary properties of hemp fibers are improved, i.e. capillary rise height of modified fibers is increased up to 2.7 times in relation to unmodified fibers. Furthermore, hemicelluloses removal increases the moisture sorption and decreases the water retention values of hemp fibers, while lignin removal decreases the moisture sorption and increases the water retention ability of hemp fibers.     

Increased transmission potential of Leishmania major/Leishmania infantum hybrids

Development of Leishmania infantum/Leishmania major hybrids was studied in two sand fly species. In Phlebotomus papatasi, which supported development of L. major but not L. infantum, the hybrids produced heavy late-stage infections with high numbers of metacyclic promastigotes. In the permissive vector Lutzomyia longipalpis, all Leishmania strains included in this study developed well. Hybrids were found to express L. major lipophosphoglycan, apparently enabling them to survive in P. papatasi midgut. The genetic exchange of the hybrids thus appeared to have enhanced their transmission potential and fitness. A potentially serious consequence is the future spread of the hybrids using this peridomestic and antropophilic vector.     

Effects of different dietary regimes alone or in combination with standardized Aronia melanocarpa extract supplementation on lipid and fatty acids profiles in rats

This study investigated different dietary strategies, high-fat (HFd), or standard diet (Sd) alone or in combination with standardized Aronia melanocarpa extract (SAE), as a polyphenol-rich diet, and their effects on lipids and fatty acids (FA) in rats with metabolic syndrome (MetS). Wistar albino rats were randomly divided into two groups: healthy and rats with MetS, and then depending on dietary patterns on six groups: healthy rats fed with Sd, healthy rats fed with Sd and SAE, rats with MetS fed with HFd, rats with MetS fed with HFd and SAE, rats with MetS fed with Sd, and rats with MetS fed with Sd and SAE. 4 weeks later, after an overnight fast (12–14 h), blood for determination of total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), index of lipid peroxidation (measured as TBARS), and FA was collected. Increased FA and lipid concentration found in MetS rats were reduced when changing dietary habits from HFd to Sd with or without SAE consumption. Consumption of SAE slightly affects the FA profiles, mostly palmitoleic acid in healthy rats and PUFA in MetS?+?HFd rats. Nevertheless, in a high-fat diet, SAE supplementation significantly decreases n-6/n-3 ratio, thereby decreasing systemic inflammation. Further researches are warranted to confirm these effects in humans.