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The necessity of anti-inflammatory drugs such as glucocorticoids has been evident during the COVID-19 pandemic. Glucocorticoids, are the standard therapy for the treatment of moderate and severe COVID-19 patients. However, serious side effects limit the use of these drugs, and anti-inflammatory drugs with better pharmacological properties are urgently required. Bile acids are of interest, because of their anti-inflammatory and immunomodulatory properties, facilitated through an unclear mechanism involving transmembrane and nuclear receptors. In this work, we screened the binding activity of a number of bile acid derivatives, for the ligand-binding domain of glucocorticoid receptor (GR-LBD), the most important receptor for anti-inflammatory processes. Tested compounds include oximes, lactones, lactams, tetrazoles, dienones, C-24 alcohols and cholic acid amides. Cholic acid oxime, deoxycholic acid dienone, 3-keto-24-cholic alcohol and cholic acid amide showed best binding affinities for GR-LBD among tested compounds. The in silico molecular docking explanation is provided. SAR analysis showed that expansion of B and C steroid rings or attachment of heterocycle to C ring is not beneficial for binding; side chain should contain hydrogen donor group; the GR-LBD tolerate well different functionalities on C-3 position. These results provide valuable information toward synthesis of the new glucocorticoids based on bile acids.

Steroids are good candidates for drug development, thanks to their low general toxicity and possibility for structure modifications connected with change of their activity. Several 16,17-secoandrost-4-ene-16,17a-dinitrile compounds were synthesized and screened for anticancer effect previously, including 6-oxo and 6-hydroxyimino compounds. This research is continued with the attempts for different synthetic strategy and evaluation of anticancer effect mechanism. Synthesis of 3-hydroxyimino compounds was successful, but inseparable mix of isomers was excluded from biological tests. Tested secodinitriles expressed cytotoxic effect on HeLa cervix cancer cells as a model system, with submicromolar to molar IC50 values, where 6-substituted derivatives were more effective. After 72 h treatment with equitoxic concentrations equal IC50 values of test compounds the mechanism of this effect was studied using flow cytometry and specific fluorescent dyes. Modest change in both G0/G1 and G2/M resting phases and change in mitochondrial membrane potential were noticed, while the most pronounced effect was apoptosis induction. Total apoptosis was in range 50.72–58.31 % in all cell samples treated with secodinitriles, compared to 7.44 % in control samples. Total percent of dead cells, including both apoptotic and necrotic, ranged from 55.24 to 65.34 %, compared to 10.68 % in control. Selectivity towards cancer cells is very important feature of these compounds indicating their potential use as lead compounds in the drug development for the treatment of cancers of steroid hormone-dependent tissues.

Homoandrostane derivatives, as compounds with significant bioactivity, were studied in terms of their chromatographic behavior in reversed-phase ultra-high performance liquid chromatography (RP-UHPLC). In the present study, five androstane derivatives from the series of homoandrostanes were analyzed, including: 3β-hydroxy-17-oxa-17a-homoandrost-5-en-16-one, 3β,5α-dihydroxy-17- oxa-17a-homoandrostane-6,16-dione, 17-oxa-5β,6β-epoxy-17a-homoandrostane-3,16-dione, 5α-hydroxy- 17-oxa-17a-homoandrostane-6,16-dione-3β-yl acetate and 3β-hydroxy-17-oxa-5α,6α-epoxy-Dhomoandrostan- 16-one. The compounds were analyzed by applying methanol-water mobile phases with different volume fractions of methanol, as a polar protic solvent, and logk0 parameters of each compound were determined. The outstanding correlations between in silico logP descriptors and logk0 parameters were obtained, as well as between in silico logD descriptors and logk0 parameters. The logk0 parameters are very well correlated with polar surface area (PSA) descriptor as well. The studied compounds and lipophilicity descriptors (including the chromatographic lipophilicity parameters - logk0) were clustered applying hierarchical cluster analysis (HCA) in the form of clustered heat map known as double dendrogram. Furthermore, the sum of ranking differences (SRD) method was used for the ranking of the lipophilicity measures of the analyzed homoandrostane derivatives so the most suitable lipophilicity measures of this series of compounds can be selected.

Coronaviruses are continually evolving, as evidenced by the emergence of three closely related pathogenic variants over the past two decades: SARS (2002), MERS (2012), and SARS‐CoV‐2 (2019); and the appearance of many new SARS‐CoV‐2 strains during the COVID‐19 pandemic. Hence, COVID‐19 has now become a pandemic disease; with a real possibility for the emergence of new deadly SARS‐related coronaviruses. The SARS‐CoV‐2 main protease, Mpro is an attractive drug target for the development of inhibitors against SARS type and other coronaviruses because it is essential for the viral life cycle and highly conserved among a wide range of pathogenic coronaviruses. This motivated the synthesis of novel inhibitors of Mpro, which could be the basis for COVID‐19 drug development. The synthesis of new 5,6 : 16,17‐diseco and 6,7 : 16,17‐disecoandrostane 16,17a‐dinitriles is reported. In silico ADMET analyses suggest that the synthesized compounds possess drug‐like properties with no predicted toxicities. Structural similarity analyses indicates that synthesized B,D‐diseco 16,17a‐dinitrile derivatives have potential as protease inhibitors. Molecular docking simulations suggest that B,D‐diseco 16,17a‐dinitriles could inhibit substrate binding by Mpro. The present study suggests that newly synthesized androstane 5,6 : 16,17‐diseco‐5‐keto‐6‐oic acid and 6,7 : 16,17‐diseco‐6,7‐dioic acid 16,17a‐dinitriles 8 and 11 could represent a starting point for the design of Mpro inhibitors against SARS type coronaviruses. [ABSTRACT FROM AUTHOR]

Dealing with the analysis of the values and locus of control, the questionnaire for measuring internal locus of control and the scale for measuring preferences of lifestyles was applied on the sample of 1,146 students. The results confirmed the relation of the value orientations and locus of control in students and pointed out statistically significant differences in students from different faculties regarding lifestyle and internal locus of control. It was confirmed that, according to the lifestyle variable, students of theology show statistically different results from other students. Domination and religiousness bring about this difference to the highest level. The results of analyses in the area of internal locus of control suggest that students from the Faculty of Theology are significantly different from the others in relation to the passive strategy of facing problems.

Psychological well-being is a significant determinant of mental health and success in profession of future class and preschool teachers. Hence, it is extremely important to investigate the individual factors that contribute to it. The aim of this research is to determine the contribution of personality traits, self-esteem and the locus of control in predicting the degree of subjective well-being in future class and preschool teachers. The sample included 418 students. The following instruments were used in the research: the Short Subjective Well-being Scale (KSB), the Big Five Plus Two questionnaire (VP+2), Rosenberg’s Self-Esteem Scale and the Scale for Measuring the Locus of Control (LO K IM-2). The results indicate that all three investigated categories of individual factors significantly predict the affective (64% of variance explained) and cognitive component (51% of variance explained) of subjective wellbeing, whereby personality traits proved to be the most important predictors. Neuroticism and extraversion contribute most to positive affectivity (Nβ=-0,801; Eβ=- 0,794) and a positive attitude towards life (Nβ=-0,701; Eβ=-0,736). The educational implications refer to the possibilities of encouraging and developing those individual personality traits that significantly contribute to subjective well-being of future class and preschool teachers. In this way, we can also contribute to their mental health, which is the necessary precondition of the accomplishment of educational work.

The aim of the study was to examine the relation between metacognitive components, declarative and procedural metacognitive knowledge and cognitive regulation, and preschool children’s performance in different problem solving tasks – hidden pictures, classifying and sorting, the same and the different, estimation, patterns, dot-to-dot, mazes and memory tasks. The sample consisted of 347 preschool children aged 3–6. The results showed that children with highly developed metacognitive abilities, declarative and procedural metacognitive knowledge, cognitive monitoring and self-regulation of cognitive strategies, were more successful and efficient in resolving problem tasks. This relation was stronger in older children and in more complex tasks.

A family is the original, primary, and the most universal social group, which implies the synthesis of several subsystems. Parents and children, children and children, as well as subsystems that are formed between children and each parent, are, in particular, the basic structural units of the family. Within each subsystem there is a two-way interaction that implies certain affective relationships, as the most important determinants in the functioning and formation of a child's personality. In its development, a family goes through the different phases that are marked by a lesser or greater influence of tradition in family relations. Traditional relationships and values include those characteristic of a patriarchal family. Modern family is a consequence of the general industrialization of society. From the production, a family is transformed into a consumer social group. Modern, postmodern, global society marks the high rate of change, the disappearance of many orientations that shaped the lives of people and families. A modern family goes through a phase of intensive changes, mostly due to the global social transformations. Elements of a traditional family organization are still not fully overcome, although new models and patterns of behavior imposed by the modern lifestyle and the modern era are present. For this reason, the main goal of this study was to examine the perceptions of family and family life of student population through analysis of the basic dimensions of family life, describing elements of traditional and modern in the current family context. The sample consisted of 504 students. The Scale of family life dimensions, designed for the purposes of this study, has shown satisfactory psychometric characteristics. The results of this study confirmed the initial research hypotheses that the current family context in which youth is growing up is characterized in a certain extent by characteristics of traditional family values, but at the same time, by characteristics of the modern family as well, with the characteristics of the new era. In such conditions, the risk of general social confusion and questioning of the basic principles and values that a family should represent are particularly prominent. These findings have significant social and pedagogical implications, which are primarily reflected in the current family environment in which young people grow up and adopt family values and norms of behavior.

Given the present generation gap between the children and the youth on one hand, and the elderly population on the other, in this paper the results of recent studies in our community dealing with these problems will be presented, and the pedagogical guidelines from which we should start to work with children and young people in the aim of raising the quality of their relation to the elderly to a higher level will be provided. By reviewing the literature dealing with the relationship of the young people to the elderly population in our community, and also by direct insight into the current situation in the society, we can observe a negative relation of the young to the old people and the aging, in all key areas of life, such as family, education, training, work etc. Fostering the correct attitude towards the elderly and encouraging mutual respect and understanding is crucial, both for the proper psychosocial development of children and young people, their education and upbringing in the desired direction, and for the quality of life and psychological well-being of the elderly population. The main objective of this paper is to reveal the actual relationship of children and young people to older people in our society, through the findings of different studies that have dealt with this problem in our community, above all, to encourage the creating of appropriate pedagogical development programs that would improve the quality of relation of the young to the old people, which will significantly contribute to the education and upbringing of the future generations.

The results of an empirical research on national identity and its components are presented in this paper. National identity was measured by the scale NAIT-K, which contains National identity scale NAIT with elements of MEIM (Phinney, 1992) and National identity scale (Cinnirella, 1997). Both instruments had high results for Cronbach alfa (α=0,92; α=0,87). In addition to these instruments, socio-demographic questionnaire was also used. On the sample of 209 students at Faculty of Philosophy in Zagreb, results indicated medium strong national identity. The factor analysis of the structure of national identity measured by NAIT-K isolated five components. We defined them as: strong national identity, nationalism, cosmopolitism, conative dimension of national identity and nation loyalty as a form of traditional heritage. Statistically significant differences are determined in analyses of national identity and religiosity. It was shown that religious respondents have stronger national identity compared to nonreligious ones.

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A simple synthesis of mono- and bis-salicylic acid derivatives 1-10 by the transesterification of methyl salicylate (methyl 2-hydroxybenzoate) with 3-oxapentane-1,5-diol, 3,6- dioxaoctane-1,8-diol, 3,6,9-trioxaundecane-1,11-diol, propane-1,2-diol or 1-aminopropan- 2-ol in alkaline conditions is reported. All compounds were tested in vitro on three malignant cell lines (MCF-7, MDA-MB-231, PC-3) and one non-tumor cell line (MRC- 5). Strong cytotoxicity against prostate PC-3 cancer cells expressed compounds 3, 4, 6, 9 and 10, all with the IC50 less than 10 μmol/L, which were 11-27 times higher than the cytotoxicity of antitumor drug doxorubicin. All tested compounds were not toxic against the non-tumor MRC-5 cell line. Antioxidant activity of the synthesized derivatives was also evaluated. Compounds 2, 5 and 8 were better OH radical scavengers than commercial antioxidants BHT and BHA. The synthesized compounds showed satisfactory scavenger activity, which was studied by QSAR modeling. A good correlation between the experimental variables IC50 DPPH and IC50 OH and MTI (molecular topological indices) molecular descriptors and CAA (accessible Connolly solvent surface area) for the new compounds 1, 3, and 5 was observed.

An efficient synthesis of several A- and B-modified D-homo lactone androstane derivatives from 3β-hydroxy-17-oxa-D-homoandrost-5-en-16-one (1) is reported. 17-Oxa-Dhomoandrost- 4-ene-3,16-dione (2), obtained by the Oppenauer oxidation of compound 1, was converted via the unstable intermediate 3,16-dioxo-4,17-dioxa-D-homoandrostane- 5α-carboxaldehyde (3) to 17-oxa-D-homo-3,5-seco-4-norandrostan-5-one-3-carboxylic acid (4), which was also obtained directly from compound 2. Compound 1 was acetylated to give 17-oxa-D-homoandrost-5-en-16-on-3β-yl acetate (5) which was then oxidized with chromium(VI)-oxide in 50% acetic acid or with meta-chlorperbenzoic acid and chromium(VI)-oxide to yield compounds 6-8 and 5α-hydroxy-17-oxa-D-homoandrostane- 6,16-dion-3β-yl acetate (9), respectively. The oximination of compound 9 gave a mixture of 6(E)-hydroximino-5α-hydroxy-17-oxa-D-homoandrostan-16-on-3β-yl acetate (10) and 6(Z)-hydroximino-5α-hydroxy-17-oxa-D-homoandrostan-16-on-3β-yl acetate (11), the hydrolysis of which gave 6(E)-hydroximino-3β,5α-dihydroxy-17-oxa-D-homoandrostan- 16-one (12) and 6(Z)-hydroximino-3β,5α-dihydroxy-17-oxa-D-homoandrostan-16-one (13). 6-Nitrile-17-oxa-5,6-seco-D-homoandrostane-5,16-dion-3β-yl acetate (14) was obtained under the Beckmann fragmentation of compounds 10 and 11. Only pure and stable compounds (1, 2, 4, 5, 9 and 14) were tested in vitro on six malignant cell lines (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, K562) and one non-tumor MRC-5 cell line. Significant antiproliferative activity against MDA-MB-231 cells showed compounds 1, 5 and 9, while compound 2 exhibited a strong antiproliferative activity. Only compound 14 showed weak antiproliferative activity against MCF-7 cells. All tested compounds were not toxic on MRC-5 cells, whereas Doxorubicin was highly toxic on these cells. [Projekat Ministarstva nauke Republike Srbije, br. 172021]

The work concerns the reactivity of 17β-hydroxy-17α-substituted androstanes 1-9. Depending on the nature of the 17α-substituent, the presence of the neighboring 16-oximino group, and the reagent used, these compounds can undergo retroaddition (10-12) and fragmentation-cyclization (14-16) reactions.

Starting from 3β-acetoxy-17-oxo-16,17-secoandrost-5-ene-16-nitrile (1), 3β-acetoxy-16,17-secoandrost-5-ene-16-nitrile (4) was synthesized by a three-stage procedure. First, the formyl group of compound 1 was reduced, to yield the alcohol 2. Compound 2 was further transformed to the mesyloxy derivative 3, whose reduction with NaBH3CN gave compound 4. Apart from compound 4 as the main reaction product, two additional products were obtained, for which the GC/MS analysis suggested that they are 8(14) and 14 derivatives of compound 4. Compound 4 was transformed into 3β-hydroxy-16,17-sesoandrost-5-ene-16-nitrile (7), the Oppenauer oxidation of which afforded 3-oxo-16,17-secoandrost-4-ene-16-nitrile (8).

The new conjugates of selected bile acids (hyocholic (2), deoxycholic (3), hyodeoxycholic (4) and 12-ketocholic (5) acids) with ethyl 11-aminoundecanoate 7, 8, 11, and 13 were synthesized. The conjugation reaction was carried out in ethyl acetate in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) and triethylamine. Under the same experimental conditions, the conjugation reaction involving ethyl 6-aminohexanoate resulted in formation of a conjugate 9 only in the case of deoxycholic acid (3) in addition to the unexpected ethyl ester 10. In the case of the other bile acids (cholic (1), hyodeoxycholic (4) and 12-ketocholic (5) acids) only an unexpected ester formation took place giving esters 6, 12, and 14. Cytotoxic activity against four tumor cell lines (human breast adenocarcinoma ER-, MDA-MB-231; breast adenocarcinoma ER+, MCF-7; cervix epiteloid carcinoma, HeLa S-3; and prostate cancer, PC-3) was evaluated. Conjugate 8 showed strong activity against HeLa S-3 and conjugate 11 for PC-3. Ethyl ester of 12-ketocholic acid 14 showed very strong antiproliferative activity against MCF-7 and HeLa S-3.

In this paper two synthetic routes for obtaining D-homo-D-aza estratriene derivatives were described. Namely, starting from 3-methoxyestra-1,3,5(10)-trien-16-oximino-17-one (1) 3-methoxy-17-aza-D-homoestra-1,3,5(10)-triene (5) was synthesized in two step. Another D-aza derivative was synthesize, starting from 3-methoxy-17-oxo-16,17-secoestra-1,3,5(10)-trien-16-nitrile (6). For that purpose, the seco-cyanoaldehyde was converted into its 17-ethylenacetal 7 followed by subsequent reduction of the nitrile function with sodium borohydride in the presence of cobalt chloride hexahydrate. Finally, under acidic conditions the obtained 16-amino-17-ethylenacetal 8 was transformed into 3-metoxy-17-aza-D-homoestra-1,3,5(10),17(17a)-tetraene (9).

Starting from 3β-acetoxy-15-cyano-17-oxo-16,17-seco-5-androstene (2) and 3β-acetoxy- 15-cyano-17-hydroxy-17-methyl-16,17-seco-5-androstene (11), new 17-halo-derivatives (5–10 and 13) were obtained. The fluoro derivative 5 was obtained from 17-tosylate 4 in reaction with tetrabutylammonium fluoride. The structure of the 17-iodo-devitive 10 was unambiguously proved by the appropriate X-ray structural analysis. Compounds5–10, as well as 12 and 13 were tested for possible anti-aromatase activity, whereby only compound 9 with bromine as the C-17 substituent, induced 19.4 % inhibition of aromatase activity compared to the control.

The multistage syntheses of the p-toluenesulphonyloxy esters (1-benzyloxy-4-p-toluenesulphonyloxybutane (3a) 1-benzyloxy-6-p-toluenesulphonyloxyhexane (3b) and 1-benzyloxy-10-p-toluenesulphonyloxydecane (3c)(, alkyl chlorides (1-benzyloxy-4-chlorobutane (4a), 1-benzyloxy-6-chlorohexane (4b) and 1-benzyloxy-10-chlorodecane (4c)(, as well as alkyl iodides (1-benzyloxy-4-iodobutane (5a), 1-benzyloxy-6-iodohexane (5b) and 1-benzyloxy-10-iododecane (5c)( with the terminal O-benzyl groups starting from 1,4-butanediol (1a), 1,6-hexanediol (1b) and 1,10-decanediol (1c) were carried out. The possibilities of formation and addition of the corresponding Grignard reagent to the C-17 carbonyl group of dehydroepiandrosterone were investigated.