Combinatorial Chemistry & High Throughput Screening - Volume 23, Issue 5, 2020

Aim and Objective: In the last decades, cancer has become a major problem in public health all around the globe. Chimeric chemical structures have been established as an important trend on medicinal chemistry in the last years. Thiazacridines are hybrid molecules composed of a thiazolidine and acridine nucleus, both pharmacophores that act on important biological targets for cancer. By the fact it is a serious disease, seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized, characterized, analyzed by computer simulation and tested in tumor cells. In order to find out if the compounds have therapeutic potential. Materials and Methods: Seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized through Michael addition and Knoevenagel condensation strategies. Characterization was performed by NMR and Infrared spectroscopy techniques. Regarding biological activity, thiazacridines were tested against solid and hematopoietic tumoral cell lines, namely Jurkat (acute T-cell leukemia); HL-60 (acute promyelocytic leukemia); DU 145 (prostate cancer); MOLT-4 (acute lymphoblastic leukemia); RAJI (Burkitt's lymphoma); K562 (chronic myelogenous leukemia) and normal cells PBMC (healthy volunteers). Molecular docking analysis was also performed in order to assess major targets of these new compounds. Cell cycle and clonogenic assay were also performed. Results: Compound LPSF/AA-62 (9f) exhibited the most potent anticancer activity against HL-60 (IC50 3,7±1,7 μM), MOLT-4 (IC50 5,7±1,1 μM), Jurkat (IC50 18,6 μM), Du-145 (IC50 20±5 μM) and Raji (IC50 52,3±9,2 μM). While the compound LPSF/AA-57 (9b) exhibited anticancer activity against the K562 cell line (IC50 51,8±7,8 μM). Derivative LPSF/AA-62 (9f) did not interfere in the cell cycle phases of the Molt-4 lineage. However, the LPSF/AA-62 (9f) derivative significantly reduced the formation of prostate cancer cell clones. The compound LPSF/AA-62 (9f) has shown strong anchorage stability with enzymes topoisomerases 1 and 2, in particular due the presence of chlorine favored hydrogen bonds with topoisomerase 1. Conclusion: The 3-(acridin-9-ylmethyl)-5-((10-chloroanthracen-9-yl)methylene)thiazolidine-2,4-dione (LPSF/AA-62) presented the most promising results, showing anti-tumor activity in 5 of the 6 cell types tested, especially inhibiting the formation of colonies of prostate tumor cells (DU-145).

Background: Neonatal sepsis is a serious and difficult-to-diagnose systemic infectious disease occurring during the neonatal period. Objective: This study aimed to identify potential biomarkers of neonatal sepsis and explore its underlying mechanisms. Methods: We downloaded the neonatal sepsis-related gene profile GSE25504 from the NCBI Gene Expression Omnibus (GEO) database. The differentially expressed RNAs (DERs) were screened and identified using LIMMA. Then, the functions of the DERs were evaluated using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, a competing endogenous RNA (ceRNA) network was constructed and functional analyses were performed. Results: The initial screening identified 444 differentially expressed (DE)-mRNAs and 45 DElncRNAs. GO analysis showed that these DE-mRNAs were involved in immune response, defense response, and positive regulation of immune system process. KEGG analysis showed that these DE-mRNAs were enriched in 30 activated pathways and 6 suppressed pathways, and those with the highest scores were the IL-17 signaling pathway and ribosome. Next, 722 miRNAs associated with the identified lncRNAs were predicted using miRWalk. A ceRNA network was constructed that included 6 lncRNAs, 11 mRNAs, and 55 miRNAs. In this network, HCP5, LINC00638, XIST and TP53TG1 were hub nodes. Functional analysis of this network identified some essential immune functions, hematopoietic functions, osteoclast differentiation, and primary immunodeficiency as associated with neonatal sepsis. Conclusion: HCP5, LINC00638, TP53TG1, ST20-AS1, and SERPINB9P1 may be potential biomarkers of neonatal sepsis and may be useful for rapid diagnosis; the biological process of the immune response was related to neonatal sepsis.

Background: Tumor microenvironment (TME) cells play important roles in tumor progression. Accumulating evidence show that they can be exploited to predict the clinical outcomes and therapeutic responses of the tumor. However, the role of immune genes of TME in small cell lung cancer (SCLC) is currently unknown. Objective: To determine the role of immune genes in SCLC. Methods: We downloaded the expression profile and clinical follow-up data of SCLC patients from Gene Expression Omnibus (GEO), and TME infiltration profile data of 158 patients using CIBERSORT. The correlation between TME phenotypes, genomic features, and clinicopathological features of SCLC was examined. A gene signature was constructed based on TME genes to further evaluate the relationship between molecular subtypes of SCLC with the prognosis and clinical features. Results: We identified a group of genes that are highly associated with TME. Several immune cells in TME cells were significantly correlated with SCLC prognosis (p<0.0001). These immune cells displayed diverse immune patterns. Three molecular subtypes of SCLC (TMEC1-3) were identified on the basis of enrichment of immune cell components, and these subtypes showed dissimilar prognosis profiles (p=0.03). The subtype with the best prognosis, TMEC3, was enriched with immune activation factors such as oncogene M0, oncogene M2, T cells follicular helper, and T cells CD8 (p<0.001). The TMEC1 subtype with the worst prognosis was enriched with T cells CD4 naive, B cells memory and Dendritic cells activated cells (p<0.001). Further analysis showed that the TME was significantly enriched with immune checkpoint genes, immune genes, and immune pathway genes (p<0.01). From the gene expression data, we identified four TME-related genes, GZMB, HAVCR2, PRF1 and TBX2, which were significantly associated with poor prognosis in both the training set and the validation set (p<0.05). These genes may serve as markers for monitoring tumor responses to immune checkpoint inhibitors. Conclusion: This study shows that TME features may serve as markers for evaluating the response of SCLC cells to immunotherapy.

Background: Since the last few decades, the healthcare sector is facing the problem of the development of multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) infections all over the world. Regardless of the current healthcare progress for the treatment of mycobacterial infections, we are still unable to control addition of every year 9 million new cases of tuberculosis (TB). Objective: We had an objective to synthesize some novel hydrazones, which were further subjected to characterization, Photoluminescence study, in vitro anti-mycobacterium testing and in silico ADMET predictions. Methods: Some new hydrazone derivatives have been successfully prepared by the condensation reaction in the present study. All the compounds were characterized by using FTIR, NMR, UV, Fluorescence spectroscopic techniques. Results: All our newly synthesized compounds showed strong electronic excitation at 292.6 – 319.0 nm and displayed more intense emissions in the 348 – 365 nm regions except compound 3i. The newly synthesized hydrazones 3a, 3b, 3f and 3g were found to be the most active compounds and showed MIC (Minimum inhibitory concentrations) values of 12.5 μg/mL. Conclusion: In the realm of development of more potent, effective, safer and less toxic antituberculosis agents; our current study would definitely help the medicinal chemists to develop potent analogues containing hydrazine motifs in them.

Aim and Objective: The Dendrobium officinalis flower (DOF) is popular in China due to common belief in its anti-aging properties and positive effects on “nourish yin”. However, there have been relatively few confirmatory pharmacological experiments conducted to date. The aim of this work was to evaluate whether DOF has beneficial effects on learning and memory in senescent rats, and, if so, to determine its potential mechanism of effect. Materials and Methods: SD rats were administrated orally DOF at a dose of 1.38, or 0.46 g/kg once a day for 8 weeks. Two other groups included a healthy untreated control group and a senescent control group. During the 7th week, a Morris water maze test was performed to assess learning and memory. At the end of the experiment, serum and brain samples were collected to measure concentrations of antioxidant enzymes, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH-Px) in serum, and the neurotransmitters, including γ-aminobutyric acid (γ-GABA), Glutamic (Glu), and monoamine oxidase B (MAO-B) in the brain. Histopathology of the hippocampus was assessed using hematoxylin-eosin (H&E) staining. Results: The results suggested that treatment with DOF improved learning as measured by escape latency, total distance, and target quadrant time, and also increased levels of γ-GABA in the brain. In addition, DOF decreased the levels of MDA, Glu, and MAO-B, and improved SOD and GSHPx. Histopathological analysis showed that DOF also significantly reduced structural lesions and neurodegeneration in the hippocampus relative to untreated senescent rats. Conclusion: DOF alleviated brain aging and improved the spatial learning abilities in senescent rats, potentially by attenuating oxidative stress and thus reducing hippocampal damage and balancing the release of neurotransmitters.

Background: Osteosarcoma is one of the most serious primary malignant bone tumors that threaten the lives of children and adolescents. However, the mechanism underlying and how to prevent or treat the disease have not been well understood. Aims and Objective: This aim of the present study was to identify the key genes and explore novel insights into the molecular mechanism of miR-542-3p over-expressed Osteosarcoma. Materials and Methods: Gene expression profile data GDS5367 was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were screened using GEO2R, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the DAVID database. And protein-protein interaction (PPI) network was constructed by the STRING database. In addition, the most highly connected module was screened by plugin MCODE and hub genes by plugin CytoHubba. Furthermore, UALCAN and The Cancer Genome Atlas were performed for survival analysis. Result: In total, 1421 DEGs were identified, including 598 genes were up-regulated and 823 genes were down-regulated. GO analysis showed that DEGs were classified into three groups and DEGs mainly enriched in Steroid biosynthesis, Ubiquitin mediated proteolysis and p53 signaling pathway. Six hub genes (UBA52, RNF114, UBE2H, TRIP12, HNRNPC, and PTBP1) may be key genes with the progression of osteosarcoma. Conclusion: The results could better understand the mechanism of osteosarcoma, which may facilitate a novel insight into treatment targets.

Aims and Objective: The common disease of insomnia has complex and diverse clinical manifestations. Lavender represents an effective treatment of insomnia, but the molecular mechanism underlying the effectiveness of this treatment is not clear. The purpose of this study is to investigate the active components, target proteins and molecular pathways of lavender in the treatment of insomnia, thus explaining its possible mechanism. Materials and Methods: Firstly, 54 active components of lavender were identified by gas chromatography-mass spectrometry (GC-MS). The target protein of lavender was predicted by the Traditional Chinese Medicine System Pharmacological Database and Analysis Platform and the SwissTargetPredicating tool, and the target protein of insomnia was predicted by the DisGeNET and DrugBank databases. Then, the "component-target-disease" network diagram was constructed using the Cytoscape 3.7.1 software. KEGG and GO enrichments were analyzed using the R statistical language. Finally, the key target proteins were verified by collecting and verifying the target protein GEO data using the Discovery Studio 3.5 molecular docking verification software. Results: 906 target proteins of lavender were predicted by the Traditional Chinese Medicine System Pharmacological Database and Analysis Platform and the SwissTargetPredicating tool, and 182 insomnia target proteins were predicted by the DisGeNET and DrugBank databases. The results of GO enrichment analysis showed that it included the reaction process of ammonium ion, the regulation of the membrane potential and the secretion of catecholamine, while the results of KEGG enrichment included the calcium signaling pathway, serotonin synapse, morphine addiction and many more. Finally, using the Discovery Studio3.5 molecular docking verification software, it was verified that the key target proteins are ADRB1 and HLA-DRB1. Conclusion: The components in the lavender essential oil include the Ethyl 2-(5-methyl-5-vinyltetrahydrofuran- 2-yl)propan-2-ylcarbonate (0.774); 5-Oxatricyclo[8.2.0.04,6]dodecane, 4,12,12-trimethyl- 9-methylene-, (1R,4R,6R,10S)-(0.147); P-Cymen-7-ol (0.063); .alpha-Humulenem (0.317); Acetic acid, hexyl ester (1.374); etc. The role lavender plays in the treatment of insomnia might be accomplished through the regulation of the key targets ADRB1 and HLA-DRB1.

Aims and Objective: This paper aims to reveal the useful industrial aspects of kandite and montmorillonite group of clays using as a catalyst after acid activation. A comparative study of modified characteristics of clay samples has been explored based on industrial requirements. Materials and Methods: In this study sodium bentonite and kaolin clay have been focused. The modified characteristics of clay samples are investigated by characterization methods of FT-IR, XRD, SEM/EDAX, TGA and DSC before and after treated with 4M of Hydrochloric acid. Clay samples were refluxed at 105ºC and calcined at 500ºC consecutively for 3 hours at room temperature. Results: Maximum crystalline size 104.02 nm has been evaluated for acid-activated sodium bentonite. Alkyl halides compounds have a strong band position for all samples and have more extent on acid activation. The small numbers of manganese particles have been noticed in the acidactivated samples. 14% of decrement and 61.02% of increment of aluminates have been found respectively for acid-activated kaolin and acid-activated sodium bentonite. Conclusion: The novelty of this study is about sodium bentonite characterization and the results show the prominent behaviour with structural, elemental, morphological, and thermal analysis. Acid-activated kaolin sample has less effect in comparison with acid-activated sodium bentonite. As the removal of the hydroxyl group of compounds has been reported through FT-IR and XRD analysis also some other industries like ceramic and paper industries may have accepted these types of modified minerals for special production with a simple process.

Aims and Objective: In this work, pyran derivatives were synthesized via a multicomponent reaction of ninhydrin, α-haloketones, dialkyl acetylenedicarboxylate, and triphenylphosphine in the presence of iron oxide magnetic nanoparticles (Fe3O4-MNPs) as efficient nanocatalyst in ethanol at room temperature. Materials and Methods: The biosynthesis of Fe3O4-MNPs was performed by Clover Leaf water extract. In addition, antioxidant activity was examined for the prepared compounds employing DPPH radical scavenging and ferric reduction activity potential (FRAP) experiment and comparing results with synthetic antioxidants (TBHQ and BHT). Results: Compound 5b showed excellent radical trapping activity and good reducing activity relative to standards (BHT and TBHQ). Conclusion: Some advantages of this procedure are: the workup of reaction is easy and the products can be separated easily by filtration. Fe3O4-MNPs display a good improvement in the yield of the product and showed significant reusable activity.