Synthesis, Crystal Structure, and Biological Evaluation of Novel 5-Hydroxymethylpyrimidines.

Pyrimidine displays a wide array of bioactivities, and thence, it is still considered a potent unit of new drug research. Its derivative, 5-hydroxymethylpyrimidine, can be found as a scaffold of nontypical nitrogen bases in DNA and as a core of some natural bioactive compounds. In this study, we obtained a series of 5-hydroxymethylpyrimidines that vary in the 4-position by the reduction of proper esters. All compounds were characterized by spectroscopic analysis, and single-crystal X-ray diffraction was performed for some of them. Biological investigations estimated cytotoxic properties against normal (RPTEC) and cancer (HeLa, HepaRG, Caco-2, AGS, A172) cell lines. It was found that the derivatives with an aliphatic amino group at the 4-position are generally less toxic to normal cells than those with a benzylsulfanyl group. Moreover, compounds with bulky constituents exhibit better anticancer properties, though at a moderate level. The specific compounds were chosen due to their most promising IC50 concentration for in silico study. Furthermore, antimicrobial activity tests were performed against six strains of bacteria and one fungus. They demonstrated that only derivatives with at least three carbon chain amino groups at the 4-position have weak antibacterial properties, and only the derivative with 4-benzylsulfanyl constituent exhibits any antifungal action.

Ciprofloxacin and Levofloxacin as Potential Drugs in Genitourinary Cancer Treatment-The Effect of Dose-Response on 2D and 3D Cell Cultures.

INTRODUCTION: Introducing new drugs for clinical application is a very difficult, long, drawn-out, and costly process, which is why drug repositioning is increasingly gaining in importance. The aim of this study was to analyze the cytotoxic properties of ciprofloxacin and levofloxacin on bladder and prostate cell lines in vitro. METHODS: Bladder and prostate cancer cell lines together with their non-malignant counterparts were used in this study. In order to evaluate the cytotoxic effect of both drugs on tested cell lines, MTT assay, real-time cell growth analysis, apoptosis detection, cell cycle changes, molecular analysis, and 3D cultures were examined. RESULTS: Both fluoroquinolones exhibited a toxic effect on all of the tested cell lines. In the case of non-malignant cell lines, the cytotoxic effect was weaker, which was especially pronounced in the bladder cell line. A comparison of both fluoroquinolones showed the advantage of ciprofloxacin (lower doses of drug caused a stronger cytotoxic effect). Both fluoroquinolones led to an increase in late apoptotic cells and an inhibition of cell cycle mainly in the S phase. Molecular analysis showed changes in BAX, BCL2, TP53, and CDKN1 expression in tested cell lines following incubation with ciprofloxacin and levofloxacin. The downregulation of topoisomerase II genes (TOP2A and TOP2B) was noticed. Three-dimensional (3D) cell culture analysis confirmed the higher cytotoxic effect of tested fluoroquinolone against cancer cell lines. CONCLUSIONS: Our results suggest that both ciprofloxacin and levofloxacin may have great potential, especially in the supportive therapy of bladder cancer treatment. Taking into account the low costs of such therapy, fluoroquinolones seem to be ideal candidates for repositioning into bladder cancer therapeutics.

A New Pyrimidine Schiff Base with Selective Activities against Enterococcus faecalis and Gastric Adenocarcinoma.

Enterococcus faecalis is known as a significant nosocomial pathogen due to its natural resistance to many antibacterial drugs. Moreover, it was found that E. faecalis infection causes inflammation, production of reactive oxygen species, and DNA damage to human gastric cancer cells, which can induce cancer. In this study, we synthesized and tested the biological activity of a new Schiff base, 5-[(4-ethoxyphenyl)imino]methyl-N-(4-fluorophenyl)-6-methyl-2-phenylpyrimidin-4-amine (3), and compared its properties with an analogous amine (2). In the biological investigation, 3 was found to have antibacterial activity against E. faecalis 29212 and far better anticancer properties, especially against gastric adenocarcinoma (human Caucasian gastric adenocarcinoma), than 2. In addition, both derivatives were non-toxic to normal cells. It is worth mentioning that 3 could potentially inhibit cancer cell growth by inducing cell apoptosis. The results suggest that the presence of the -C=N- bond in the molecule of 3 increases its activity, indicating that 5-iminomethylpyrimidine could be a potent core for further drug discovery research.

α1 Subunit Histidine 55 at the Interface between Extracellular and Transmembrane Domains Affects Preactivation and Desensitization of the GABAA Receptor.

The GABAA receptor is a member of the Cys-loop family and plays a crucial role in the adult mammalian brain inhibition. Although the static structure of this receptor is emerging, the molecular mechanisms underlying its conformational transitions remain elusive. It is known that in the Cys-loop receptors, the interface between extracellular and transmembrane domains plays a key role in transmitting the "activation wave" down to the channel gate in the pore. It has been previously reported that histidine 55 (H55), located centrally at the interfacial ß1-ß2 loop of the α1 subunit, is important in the receptor activation, but it is unknown which specific gating steps it is affecting. In the present study, we addressed this issue by taking advantage of the state-of-the-art macroscopic and single-channel recordings together with extensive modeling. Considering that H55 is known to affect the local electrostatic landscape and because it is neighbored by two negatively charged aspartates, a well conserved feature in the α subunits, we considered substitution with negative (E) and positive (K) residues. We found that these mutations markedly affected the receptor gating, altering primarily preactivation and desensitization transitions. Importantly, opposite effects were observed for these two mutations strongly suggesting involvement of electrostatic interactions. Single-channel recordings suggested also a minor effect on opening/closing transitions which did not depend on the electric charge of the substituting amino acid. Altogether, we demonstrate that H55 mutations affect primarily preactivation and desensitization most likely by influencing local electrostatic interactions at the receptor interface.

Personality and attitudes towards people with mental disorders: Preliminary studies results.

BACKGROUND: The subject of psychological research all over the world is to understand the factors conditioning relationships between healthy people and people with mental disorders. Authors analysing attitudes towards people with mental disorders emphasize the importance of two types of determinants: personality factors and demographic and social variables. AIM: The aim of the research was to determine the interdependencies between personality traits and attitudes towards people with mental disorders, taking into account the moderating role of social distance and demographic and environmental variables. METHOD: Polish version of Community Attitudes towards Mental Illness (CAMI) - Kwestionariusz Postaw (KP) was used to measure attitudes towards people with mental disorders. Personality traits were measured using the NEO-Five-Factor Inventory (FFI) Personality Inventory by Costa and McCrae-Polish Adaptation, and the polish version of the Social Distance Scale was used to measure the declared social distance. In all, 204 people participated in the research: 133 women and 71 men, aged 18-65 years, living in the Kuyavian-Pomeranian and Greater Poland voivodeships. RESULTS: The results showed that there is a relationship between personality traits: neuroticism, extraversion, openness to experience and agreeableness and an attitude towards people with mental disorders. Social distance, as the proposed moderator, did not significantly change the relationship between the variables. CONCLUSION: The results of the research have confirmed the important role of personality factors for attitudes, what should be remembered to exploration of presented phenomenon.