K562 Cancer Cell Research Articles

The Molecular Mechanisms of Oleanane Aldehyde-β-enone Cytotoxicity against Doxorubicin-Resistant Cancer Cells.

Oleanane aldehyde-β-enone (OA), being the semi-synthetic derivative of the triterpenoid betulin, effectively inhibits the proliferation of HBL-100 and K562 cancer cells (IC50 0.47-0.53 µM), as well as the proliferation of their resistant subclones with high P-gp expression HBL-100/Dox, K562/i-S9 and K562/i-S9_Dox (IC50 0.45-1.24 µM). A molecular docking study, rhodamine efflux test, synergistic test with Dox, and ABC transporter gene expression were used to investigate the ability of OA to act as a P-gp substrate or inhibitor against Dox-resistant cells. We noted a trend toward a decrease in ABCB1, ABCC1 and ABCG2 expression in HBL-100 cells treated with OA. The in silico and in vitro methods suggested that OA is neither a direct inhibitor nor a competitive substrate of P-gp in overexpressing P-gp cancer cells. Thus, OA is able to overcome cellular resistance and can accumulate in Dox-resistant cells to realize toxic effects. The set of experiments suggested that OA toxic action can be attributed to activating intrinsic/extrinsic or only intrinsic apoptosis pathways in Dox-sensitive and Dox-resistant cancer cells, respectively. The cytotoxicity of OA in resistant cells is likely mediated by a mitochondrial cell death pathway, as demonstrated by positive staining with Annexin V-FITC, an increasing number of cells in the subG0/G1 phase, reactive oxygen species generation, mitochondrial dysfunction, cytochrome c migration and caspases-9,-6 activation.

Enhancer/gene relationships: Need for more reliable genome-wide reference sets.

Differences in cells' functions arise from differential activity of regulatory elements, including enhancers. Enhancers are cis-regulatory elements that cooperate with promoters through transcription factors to activate the expression of one or several genes by getting physically close to them in the 3D space of the nucleus. There is increasing evidence that genetic variants associated with common diseases are enriched in enhancers active in cell types relevant to these diseases. Identifying the enhancers associated with genes and conversely, the sets of genes activated by each enhancer (the so-called enhancer/gene or E/G relationships) across cell types, can help understanding the genetic mechanisms underlying human diseases. There are three broad approaches for the genome-wide identification of E/G relationships in a cell type: 1) genetic link methods or eQTL, 2) functional link methods based on 1D functional data such as open chromatin, histone mark or gene expression and 3) spatial link methods based on 3D data such as HiC. Since 1) and 3) are costly, the current strategy is to develop functional link methods and to use data from 1) and 3) as reference to evaluate them. However, there is still no consensus on the best functional link method to date, and method comparison remain seldom. Here, we compared the relative performances of three recent methods for the identification of enhancer-gene links, TargetFinder, Average-Rank, and the ABC model, using the three latest benchmarks from the field: a reference that combines 3D and eQTL data, called BENGI, and two genetic screening references, called CRiFF and CRiSPRi. Overall, none of the three methods performed best on the three references. CRiFF and CRISPRi reference sets are likely more reliable, but CRiFF is not genome-wide and CRiFF and CRISPRi are mostly available on the K562 cancer cell line. The BENGI reference set is genome-wide but likely contains many false positives. This study therefore calls for new reliable and genome-wide E/G reference data rather than new functional link E/G identification methods.

Synthesis and Biological Evaluation of Sclareolide-Indole Conjugates and Their Derivatives

Sclareolide is a sesquiterpene lactone isolated from various plant sources in tons every year and is commercially used as a flavor ingredient in the cosmetic and food industries. Antitumor and antiviral activities of sclareolide have been previously reported. However, biological studies of sclareolide synthetic analogous are few. In view of these, we developed a robust synthetic method that allows the assembly of 36 novel sclareolide-indole conjugates and their derivatives. The synthetic method was based on TiCl4-promoted nucleophilic substitution of sclareolide-derived hemiacetal 4, while electron-rich aryles including indoles, polyphenol ethers, and pyrazolo [1,5-a]pyridine were good substrates. The stereochemistry of the final products was confirmed by single-crystal X-ray diffraction analysis, while the antiproliferative activities of selected final products were tested in K562 and MV4-11 cancer cell lines. Cytometric flow analysis shows that lead compounds 8k- and 10-induced robust apoptosis in MV4-11 cancer cells, while they exhibited weak impact on cell cycle progression. Taken together, our study suggests that sclareolide could be a good template and substrate for the synthesis of novel antiproliferative compounds.

Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates

Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the ανβ3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases.

Privileged fragment-based design, synthesis and in vitro antitumor activity of imatinib analogues.

Based on the privileged fragment-based drug design strategy, a series of imatinib analogues bearing the moiety of 3-(2-amino-2-oxoacetyl)-1H-indole were designed and synthesized, and the in vitro antitumor activity of these compounds was detected by MTT method using K562 (human myeloid leukemia) and K562R (imatinib-resistant chronic myeloid leukemia) cell lines. Molecular docking was used to preliminarily explain the possible binding modes. The most potent compound I2 exhibited better antitumor activity than those of imatinib against K562 and K562R cancer cells with IC50 values of 0.8 μM and 0.7 μM.

Novel 1,2,5-Trisubstituted Benzimidazoles Potentiate Apoptosis by Mitochondrial Dysfunction in Panel of Cancer Cells.

Synthetic small molecules have been very effective in decimating cancer cells by targeting various aberrantly overexpressed oncogenic proteins. These small molecules target proteins involved in cell cycle regulation, cell division, migration, invasion, angiogenesis, and other regulatory proteins to induce apoptosis in cancer cells. In this study, we have synthesized a novel 1,2,5-trisubstituted benzimidazole chemical library of small molecules and unveiled their anticancer potential against a panel of cancer cell lines such as Jurkat, K-562, MOLT-4, HeLa, HCT116, and MIA PaCa-2 cancer cells. The MTT assay and Trypan blue dye exclusion assay clearly unveiled the cytotoxic effect of methyl 1-benzyl-2-(4-fluoro-3-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate (TJ08) and its potential to induce apoptosis with effective IC50 of 1.88 ± 0.51, 1.89 ± 0.55, 2.05 ± 0.72, 2.11 ± 0.62, 3.04 ± 0.8, and 3.82 ± 0.25 μM against Jurkat, K562, MOLT-4, HeLa, HCT116, and MIA PaCa-2 cancer cell lines, respectively. Altered mitochondrial membrane potential was observed in HeLa, HCT116, and Jurkat cells due to TJ08 treatment, which was unveiled by JC10 staining. Induction of early and late apoptosis by TJ08 treatment was also unveiled by apoptotic analysis and immunofluorescence imaging. Cell cycle analysis distribution confirms the accumulation of cells in the S-phase in a dose-dependent manner.

In vitro Antiproliferative Properties of Lipophililic-Acid Chelating Fluoroquinolones and TriazoloFluoroquinolones with 7-dihaloanilinosubstitution.

Incidence rates and prevalence of cancer are substantially high globally. New safe therapeutic drugs are endorsed to overcome the high toxicity and poor safety profile of clinical anticancer agents. As antineoplastic Vosaroxin is a commercial fluoroquinolone (FQ), we hypothesize that superlative antiproliferation activity of lipophilic FQs/TFQs series correlates to their acidic groups and C8-C7 ethylene diamine Chelation Bridge along with bulky dual halogenations. We tested dual lipophilic- acidic chelating FQs with a genuine potential of antiproliferative propensities based on their dual DPPH- and NO- radicals scavenging biocapacities using cell based - and colorimetric assays vs. respective reference agents as their molecular action mechanism. In this work, 9 lipophilic-acid chelating FQs and their cyclized TriazoloFQs (TFQs) designed to bear 7- dihaloanilino substituents with a special focus on dichlorosubstitutions have been prepared, characterized and screened against breast T47D and MCF7, Pancreatic PANC1, colorectal HT29, cervical HELA, lung A375, skin A549, and Leukaemia K562 cancer cell lines using sulforhodamine B colorimetric bioassay. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals' scavenging propensities - as their molecular action mechanism- in comparison to ascorbic acid and indomethacin, respectively. Using Griess assay in lipopolysaccharide (LPS) prompted RAW264.7 macrophages inflammation, IC50 values (μM) in the ascending order of new FQs' NO scavenging/antiinflammation capacity were 4a < 3a < 4c < indomethacin (23.8 < 33.4 < 36 vs. indomethacin's 124, respectively). Exceptionally unlike the rest, reduced FQ, 4b exhibited remarkably superior DPPH radical scavenging capacity to ascorbic acid (IC50 values (μM) 19.9 vs. 123.9, p < 0.001). In comparison to cisplatin; nitroFQs (3a, 3b and 3c), the reduced FQs (4a, 4b, and 4c) and the TFQs (5a, 5b and 5c) exerted substantial micromolar antiproliferation IC50 values < 50 μM in cervical Hela cancer cells but lacked comparable bioactivity in leukaemia K562. In both breast MCF7 and T47D cancer cell lines, FQs/TFQs 4a < 3a < 5b (respective IC50 values (μM) 0.52 < 22.7 < 24 vs. cisplatin's 41.8 and 0.03 < 4.8 < 27 vs. cisplatin's 509), and in both GI system colorectal HT29 and pancreatic PANC1 cancer cells FQs/TFQs 4a < 3a < 5b and 4a< 3a (respective IC50 values (μM) 0.12 < 3.5 < 15.9 vs. cisplatin's 148 and 1.5 < 10.4 vs. cisplatin's 25.5), exerted nanomolar-micromolar affinities of antiproliferation potencies < 50μM. Besides in lung A375 cancer cells FQs/TFQs 4c < 4a < 3a and in skin A549 cancer cells 5c < 3c < 4a < 3a < 4c (respective IC50 values (μM) 0.07 < 3.2 < 10.3 vs. cisplatin's 390 and 0.5 < 2.3 < 3.8 < 8.8 < 17.3 vs. cisplatin's 107) exhibited nanomolar-micromolar antineoplastic capacities < 50 μM. Their spectrum of selectivity indices for safety in fibroblasts PDL-based 72h incubations was reported. Unequivocally 4b reduction of viability effectiveness linked with its DPPH radical scavenging effects (without a matching antiinflammation effect). Explicitly 4a, 3a and 4c exerted exquisite antiinflammation-selective cytotoxicity duality in vitro. Such a new potential chelation mechanism can explain the pronounced difference in antineoplastic activity of new FQs/TFQs.

Synthesis and Evaluation of New Derivatives of Busulfan as an Anti-carcinogenic Drug against k562 Cancer Cells Using the AO / PI Method

Background: Busulfan is a DNA alkylating drug used to treat chronic myeloid leukemia (CML). This type of leukemia affects bone marrow cells or myocytes, which make up bone marrow tissue having a chronic process. Leukemia is a progressive and malignant disease of the body's hematopoietic organs. The disease is caused by the underdevelopment and proliferation of white blood cells and their precursors in the blood and bone marrow. Objective: The synthesis of Busulfan drug and the conjugation of Busulfan from the anomeric position of acetylated galactose as a new derivative of Busulfan and its anti-cancer effect on K562 cancer cells are among the most important objectives of this study. Methods: In this work, galactose was acetylated with acetic anhydride in the presence of sodium acetate, then the anomeric position of acetylated carbohydrate deacetylated using imidazole to obtain the final product through the reaction of Busulfan. Anti-cancer activity of the product was evaluated against K562 cancer cells. The proliferation and survival of K562 cancer cells and PBMCs (peripheral blood mononuclear cells) using the AO/PI method were studied. Furthermore, 1- (2, 3, 4, 6-tetra-O-acetyl-Iβ-D-galactopyranosyl) -4- (methyl sulfonyl oxy) butane was evaluated against cancer cells as a new derivative. Results: In this study, the Acridine Orange / Propidium Iodide (AO/PI) method was performed using fluorescence microscopy to evaluate the efficacy of a synthesized product. The effective dose of 0.02 mg/L of 1- (2, 3, 4, 6-tetra-O-acetyl-Iβ-D-galactopyranosyl) -4- (methyl sulfonyl oxy) butane was observed to cause 96% of cancer cells necrosis. Conclusion: 1- (2, 3, 4, 6-tetra-O-acetyl-Iβ-D-galactopyranosyl) -4- (methyl sulfonyl oxy) butane as a new derivative of Busulfan acts non-specifically in the cell cycle by inhibiting DNA activity by alkylation and binding to the DNA strand. Alkylating agents usually bind an alkyl group to the number seven nitrogen atom in the guanine nucleotide in a DNA molecule.

Genome-wide CRISPR Screen Reveal Targets of Chiral Gold(I) Anticancer Compound in Mammalian Cells.

Metal-based drugs, such as cisplatin and auranofin, are used for the treatment of cancer and rheumatoid arthritis, respectively. Auranofin and other gold-derived compounds have been shown to possess anticancer, anti-inflammatory, antimicrobial, and antiparasitic activity in preclinical and clinical trials. Unlike platinum agents which are known to target DNA, the target of gold is not well elucidated. To better understand the targets and effects of gold agents in mammalian cells, we used a targeted CRISPR (ToxCRISPR) screen in K562 cancer cells to identify genes that modulate cellular sensitivity to gold. We synthesized a novel chiral gold(I) compound, JHK-21, with potent anticancer activity. Among the most sensitizing hits were proteins involved in mitochondrial carriers, mitochondrial metabolism, and oxidative phosphorylation. Further analysis revealed that JHK-21 induced inner mitochondria membrane dysfunction and modulated ATP-binding cassette subfamily member C (ABCC1) function in a manner distinct from auranofin. Characterizing the therapeutic effects and toxicities of metallodrugs in mammalian cells is of growing interest to guide future drug discovery, and cellular and preclinical/clinical studies.

Sodium Danshensu mediates human T lymphocyte activation via NF‐κB and MAPK pathway regulation

AbstractSodium Danshensu (SDSS), a vital constituent of Salvia miltiorrhiza Bunge, reportedly protects the myocardium and inhibits platelet aggregation, while displaying antiatherosclerotic, hypolipidemic, and anti‐inflammatory properties. In the research, the immune regulatory influences and mechanisms of SDSS on the T lymphocytes in the human peripheral blood were investigated. The results showed that administering specific SDSS doses enhanced T lymphocyte growth, while distinctly promoting their tumor cell cytotoxicity. However, SDSS showed no effect on the proliferation of A549, HCT116, and K562 cancer cells. The gene expression of the IFN‐γ, IL‐4, IL‐2, and IL‐6 cytokines secreted by T cells was positively regulated. Furthermore, SDSS dose‐dependently facilitated phosphorylated extracellular regulated protein kinase (p‐ERK) as well as phosphorylated c‐Jun N‐terminal kinase (p‐JNK) protein expression, increased IKKβ and Ikappa B kinase α (IKKα) protein expression and decreased the nuclear factor kappa‐B kinase α (IκBα) inhibitor; negatively regulated p‐p65 protein expression in the cytoplasm, and positively in the nucleus. In addition, blockage of protein expression with specific ERK, JNK, or IκBα inhibitors significantly restricted the T lymphocyte growth induced by SDSS, identifying the specific regulatory influence of SDSS on T lymphocytes via the signaling pathways involving nuclear factor kappa‐B (NF‐κB) and mitogen‐activated protein kinase (MAPK). In conclusion, SDSS can explicitly encourage T lymphocyte propagation in the peripheral blood of humans, while enhancing their cytotoxicity by activating the pathways involving NF‐κB and MAPK.

Synthesis, Leishmanicidal, Trypanocidal, Antiproliferative Assay and Apoptotic Induction of (2-Phenoxypyridin-3-yl)naphthalene-1(2H)-one Derivatives.

The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8–23 were obtained using the classical base-catalyzed Claisen–Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.

Phytochemical characterization and evaluation of antioxidant, antimicrobial, antibiofilm and anticancer activities of ethyl acetate seed extract of Hydnocarpus laurifolia (Dennst) Sleummer.

Various functional groups were observed in the FTIR analysis of Hydnocarpus laurifolia seeds ethyl acetate extract such as O-H, N-H, C-H, -CH2, O=C=O, C=O, C=O-NH, and CH3, etc. Eleven bioactive compounds were detected via GC-MS and the predominant compounds include (1S)-2-cyclopentene-1-tridecanoicacid (chaulmoogric acid) (80.59%); 2-cyclopentene-1-undecanoic acid (hydnocarpic acid) (6.76%); cyclobutylamine (5.28%); methyl thioacetate (ethanethioic acid) (4.84%); lignoceric acid (2.21%). The TPC and TFC values were 0.110 ± 0.04 GAE g-1 and 0.175 ± 0.05g CE g-1 respectively. Ethyl acetate extract showed strong DDPH free radical scavenging activity with IC50 value 10.64 ± 0.48µgml-1 and antioxidant activity index 3.759. The ethyl acetate extract also exhibited potential ABTS radical scavenging efficacy with a very low IC50 value, i.e., 07.81 ± 0.48µgml-1. P. aeruginosa was the most sensitive bacteria to the extract with 33.16 ± 0.88mm inhibition zone and MIC: 3.12mgml-1, MBC: 6.25mgml-1. P. aeruginosa biofilm was inhibited by ethyl acetate extract 99.22% at MIC concentration. The LM images displayed a decrease in the number of biofilm cells and FE-SEM micrographs showcased the extensive decrease as well as disintegration in biofilm. Additionally, ethyl acetate extract was found selectively cytotoxic to the K562 cancer cells having an IC50 of 25.41μgml-1 and barely cytotoxic to normal PBMCs having an IC50 of 482.54μgml-1, and the selectivity index value was 18.99. Data validate scientifically the traditional use of H. laurifolia seeds in folk medicines and confirmed that it can be used in modern phytomedicines as an antioxidant, antimicrobial, antibiofilm, and anticancer agent and is toxicologically safe.

Nucleotide-Binding Oligomerization Domain 1/Toll-Like Receptor 4 Co-Engagement Promotes Non-Specific Immune Response Against K562 Cancer Cells.

Nucleotide-binding oligomerization domain 1 (NOD1) receptor and Toll-like receptor 4 (TLR4) belong to the family of pattern recognition receptors. Interactions between these receptors profoundly shape the innate immune responses. We previously demonstrated that co-stimulation of peripheral blood mononuclear cells (PBMCs) with D-glutamyl-meso-diaminopimelic acid (iE-DAP)-based NOD1 agonists and lipopolysaccharide (LPS), a TLR4 agonist, synergistically increased the cytokine production. Herein, we postulate that stimulation of NOD1 alone or a combined stimulation of NOD1 and TLR4 could also strengthen PBMC-mediated cytotoxicity against cancer cells. Initially, an in-house library of iE-DAP analogs was screened for NOD1 agonist activity to establish their potency in HEK-Blue NOD1 cells. Next, we showed that our most potent NOD1 agonist SZZ-38 markedly enhanced the LPS-induced cytokine secretion from PBMCs, in addition to PBMC- and natural killer (NK) cell-mediated killing of K562 cancer cells. Activation marker analysis revealed that the frequencies of CD69+, CD107a+, and IFN-γ+ NK cells are significantly upregulated following NOD1/TLR4 co-stimulation. Of note, SZZ-38 also enhanced the IFN-γ-induced PBMC cytotoxicity. Overall, our findings provide further insight into how co-engagement of two pathways boosts the non-specific immune response and attest to the importance of such interplay between NOD1 and TLR4.

Design and prediction of novel pyrazole derivatives as potential anti-cancer compounds based on 2D-QSAR study against PC-3, B16F10, K562, MDA-MB-231, A2780, ACHN and NUGC cancer cell lines

Despite the decades of scientific studies for developing promising new therapies, cancer remains a major cause of illness and mortality, worldwide. Several cancer types are the major topic of research in drug discovery programs due to their global incidence cases and growing frequency. In the present study, using two different statistical approaches PCA (principal component analysis) and PLS (partial least squares), six 2D-QSAR (quantitative structure activity relationship) models have been developed for the set of compounds retrieved against seven cancer cell lines vizPC-3, B16F10, K562, MDA-MB-231, A2780, and ACHN. For the creation and validation of 2D-QSAR models, OECD (Organization for Economic Co-operation and Development) requirements have been strictly followed. All of the generated 2D-QSAR models produce a significant and high correlation coefficient value with several other statistical parameters. Moreover, developed 2D-QSAR models have been used for activity predictions of in-house synthesized 63 pyrazole derivatives compounds. Precisely, most statistically significant and accepted2D-QSAR model generated for each cancer cell line has been used to predict the pIC50 value (anti-cancer activity) of all 63 synthesized pyrazole derivatives. Furthermore, designing of novel pyrazole derivatives has been carried out by substituting the essential functional groups based on the best derived 2D-QSAR models for each cancer cell line, more precisely, based on the most significant molecular descriptors with enhanced anti-cancer activity. Finally, the prediction of the new designed molecules reveals higher pIC50 than the standard compounds.

Design, synthesis and mechanistic studies of novel imidazo[1,2-a]pyridines as anticancer agents

Herein, the design, synthesis and mechanistic study of five series of imidazo[1,2-a]pyridines 8a-d, 9a-f, 11a-c, 12a-d and 14a-d as anticancer agents were discussed. The cytotoxicity of imidazo[1,2-a]pyridine derivatives was screened against NCI 60 cancer cell lines. The cytotoxicity of compounds 8b, 8c, 9e and 9f was then evaluated against leukemia K-562 cancer cell line and normal lung fibroblasts (WI38). The hydrazone derivatives 8b and 8c exhibited significant cytotoxic activities against the leukemia K-562 cancer cell line with good safety margins (IC50 = 2.91 µM, SI = 8.32 and IC50 = 1.09 µM, SI = 10.54, respectively). In addition, compounds 8b, 8c, 9e and 9f were tested for their EGFR and COX-2 inhibitory activities. The hydrazone derivatives 8b and 8c were the most active EGFR inhibitors with IC50 values of 0.123 and 0.072 µM, respectively. Compound 8c selectively inhibited COX-2 (IC50 = 1.09 µM, SI = 13.78). Moreover, the potential of compound 8c to induce apoptosis in leukemia K-562 cell line was determined. Compound 8c showed a pre-G1 apoptosis and a growth arrest of leukemia K-562 cell line at G1 phase of cell cycle. Also, compound 8c was able to induce caspase-3 overexpression (6.98 folds), if compared to control. Finally, molecular docking studies and physicochemical properties calculation of compounds 8b, 8c, 9e and 9f were carried out to explain the biological data and to predict bioavailability of the most active compounds.

Discovery of Desmuramylpeptide NOD2 Agonists with Single-Digit Nanomolar Potency.

The innate immune receptor nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) represents an important target for the development of structurally defined small molecule immunomodulatory compounds that have great potential to be used either as vaccine adjuvants or as general immunostimulatory agents. We report here the investigation of the structure–activity relationship of a series of novel desmuramylpeptide NOD2 agonists. Extensive exploration of chemical space culminated in the discovery of a lipophilic adamantane-moiety-featuring compound 40, the first single-digit nanomolar and the most potent NOD2 agonist in its structural class to date. Moreover, 40 acted synergistically with lipopolysaccharide and interferon-γ to induce the production of cytokines in human peripheral blood mononuclear cells and enhance their nonspecific cytotoxic activity against K562 cancer cells. These findings provide initial insight into its immunostimulatory potential, especially when used in combination with other immunopotentiators.

Role of plant (tulasi, neem and turmeric) extracts in defining the morphological, toxicity and catalytic properties of silver nanoparticles

Silver nanoparticles (SNPs) synthesized using tulasi, neem and turmeric aqueous extracts; both individually and in combination were characterized using various analytical techniques. None of the SNPs have shown bactericidal activity against the Coagulase-negative staphylococci (CoNS), Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. SNPs-2 (Neem) have shown highest toxic effect against HeLa (59.19 ± 2.60 µg/mL) and K-562 (60.26 ± 2.23 µg/mL) cancer cell lines, whereas SNPs-7 (Tulasi:Neem:Turmeric) has shown least toxicity (>100 µg/mL). SNPs-2 has also shown highest mortality against Artemia nauplii with LC50 value of 16.98 µg/mL after 48 h exposure, whereas SNPs-7 has shown lowest mortality (>100 µg/mL). Contrastingly, SNPs-2 has shown highest catalytic activity in the reduction of rhodamine-B (rh-B) and methyl orange (MO) dyes in the presence of sodium borohydride (SBH) as reducing agent. SNPs-2 has degraded 98.45 ± 1.35% rh-B dye under 45 min with 0.0954 min−1 (pseudo-first order rate constant), whereas 94.27 ± 1.74% reduction was observed for MO dye under 35 min with 0.0857 min−1. SNPs-7 has shown 68.93 ± 2.18% (0.0288 min−1 under 45 min) and 90.81 ± 1.87% (0.0730 min−1 under 35 min) reduction for rh-B and MO dyes, respectively.

Antiproliferative and Cytotoxic Cytochalasins from Sparticola triseptata Inhibit Actin Polymerization and Aggregation.

Laying the groundwork on preliminary structure–activity relationship study relating to the disruptive activity of cytochalasan derivatives on mammalian cell actin cytoskeleton, we furthered our study on the cytochalasans of the Dothideomycetes fungus, Sparticola triseptata. A new cytochalasan analog triseptatin (1), along with the previously described cytochalasans deoxaphomin B (2) and cytochalasin B (3), and polyketide derivatives cis-4-hydroxy-6-deoxyscytalone (4) and 6-hydroxymellein (5) were isolated from the rice culture of S. triseptata. The structure of 1 was elucidated through NMR spectroscopic analysis and high-resolution mass spectrometry (HR-ESI-MS). The relative and absolute configurations were established through analysis of NOESY spectroscopic data and later correlated with experimental electronic circular dichroism and time-dependent density functional theory (ECD–TDDFT) computational analysis. Compounds 1 and 2 showed cytotoxic activities against seven mammalian cell lines (L929, KB3.1, MCF-7, A549, PC-3, SKOV-3, and A431) and antiproliferative effects against the myeloid leukemia K-562 cancer cell line. Both 1 and 2 were shown to possess properties inhibiting the F-actin network, prompting further hypotheses that should to be tested in the future to enable a well-resolved concept of the structural implications determining the bioactivity of the cytochalasin backbone against F-actin.

Antiproliferative Activities of Lipophililic Fluoroquinolones- Based Scaffold Against a Panel of Solid and Liquid Cancer Cell Lines

Objectives:In this work, 9 lipophilic-acid chelating FQs (fluoroquinolones) comprising chelating groups have been prepared, characterized and screened for in vitro cytotoxicity, radical scavenging and antiinflammation propensities.Methods:Using sulforhodamine B colorimetric bioassay vs. cisplatin; FQs-inflicted reductions’ of viability against breast T47D and MCF7, Pancreatic PANC-1, colorectal HT29, HCT116, SW620, CACO2, SW480 and Leukaemia K562 cancer cell lines were examined in quadruplicates/dose/cell line. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals’ scavenging capacities -as their molecular action mechanism- in comparison to ascorbic acid and indomethacin respectively. Using Griess assay in Lipopolysaccharide (LPS) prompted RAW264.7 macrophages; mitigation of inflammation was investigated. Results:nitroFQ 3b, unlike the rest of FQs in PANC1 and MCF7 cells, exhibited remarkably superior NO-radical scavenging/antiinflammation capacity to indomethacin with respective antiproliferative IC50 values (<50µM) 49 vs. cisplatin’s 122 and 6 vs. cisplatin’s 28 (p<0.01-0.001; n=4). Reduced FQ 4b of significantly dual DPPH-NO scavenging propensities exerted exceptionally substantial micromolar antiproliferation in colorectal cancer cells with respective antiproliferative IC50 values (<50µM) of HCT116 0.84< HT29 1.6<PANC1 5.7<SW620 9.2 vs. cisplatins’, (p<0.01-0.001; n=4). FQ 5a of superb NO radical reduction effect had antiproliferative IC50 value (<50µM) of 37.6 in PANC1 cells. In breast cancer T47D the ascending order of pronounced nano-micromolar antiproliferative IC50 values (<50µM) was 4d<3d<4a<4b<3b (0.009<0.59<10<15<41 vs. cisplatins’, p<0.01-0.001; n=4). Both 4d and 4b displayed both DPPH-NO radicals reduction –related cytotoxicities. NO radical scavengers 3d and 3b as well as DPPH radical scavenger 4a exerted highly appreciably relevant antineoplastic affinities. Conclusion:Acidic groups and C8-C7 ethylene diamine Chelation Bridge along with bulky dual halogenations can be substantially associated with molecular action mechanisms of FQs cytotoxicities, antioxidative and antiinflammation effects, collectively.

Chemical constituent of Isochrysis galbana microalgae extract and its cytotoxic activities on leukemic cell lines

Background and Aims: This study was aimed to investigate the anti-cancer effect of Isochrysis galbana microalgae extract. Methods: In the study, the chemical composition of Isochrysis galbana microalgae extract was analyzed, and its cytotoxic effect against K562, HL60, U937, MOLT-4, and Raji cancer cells was investigated. ECV304 endothelial cells were used as a healthy cell line for the understanding of its selective cytotoxicity. To determine the effects of Isochrysis galbana extract, an MTT cytotoxicity assay was performed. Results: According to the results of the experiments, the highest cytotoxic effect of Isochrysis galbana microalgae extract was shown at about 24.07±6.48% cytotoxicity against Raji cells. There were a large number of bioactive molecules in the extract, and these molecules showed a specific response to Raji cells when considering the synergistic and antagonistic effects of these molecules on each other. Conclusion: According to the results of GC-MS analysis of Isochrysis galbana microalgae extract, the most intense molecules in the content were Dodecanoic acid, 3-hydroxy- (CAS) Beta-Hydroxy Dodecanoic Acid, and Propanoic acid, 2-methyl-, 1-(1,1-dimethylethyl)-2-methyl-1,3-isonide. The investigation of the effect of these molecules specifically against Raji cells is important to determine the possible anti-leukemic molecules and their combinations that show cytotoxicity against this cell line.