scholarly journals Synthesis and Evolution of Berberine Derivatives as a New Class of Antiviral Agents against Enterovirus 71 through the MEK/ERK Pathway and Autophagy

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2084 ◽  
Author(s):  
Yan-Xiang Wang ◽  
Lu Yang ◽  
Hui-Qiang Wang ◽  
Xiao-Qiang Zhao ◽  
Ting Liu ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Enterovirus 71 ◽  
Dependent Manner ◽  
New Class ◽  
New Family ◽  
Sar Studies ◽  
Ic50 Values ◽  
Antiviral Activities ◽  
Berberine Derivatives ◽  
Dose Dependent

Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC50 values of 7.12–14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency.

Synthesis and Assessment of Novel Anti-chlamydial Benzylidene Acylhydrazides Derivatives

2018 ◽  
Vol 15 (1) ◽  
pp. 31-36 ◽  
Author(s):  
Xiaofeng Bao ◽  
Ying Xue ◽  
Chao Xia ◽  
Yin Lu ◽  
Ningjing Yang ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dependent Manner ◽  
Iron Starvation ◽  
Hydrochloride Salt ◽  
Obligate Intracellular ◽  
Biphasic Life Cycle ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Dose Dependent ◽  
Better Than

Background: Chlamydiae, characterized by a unique biphasic life cycle, are a group of Gram-negative obligate intracellular bacterial pathogens responsible for diseases in a range of hosts including humans. Benzylidene acylhydrazide CF0001 could inhibit chlamydiae independent of iron starvation and T3SS inhibition. This finding promoted us to design and synthesize more benzylidene acylhydrazides to find novel anti-chlamydial agents. Methods: The carboxylic acids 1a-1d were coupled with Boc-hydrazide inpresence of EDCI and DMAP to obtain the intermediate 2a-2d in 60-62% yields. N-Boc deprotections were performed to obtain hydrazide hydrochloride salt 3a-3d. Nextly, the hydrazides were subjected to condensation with aldehydes to obtain benzylidene acylhydrazides 4a-4g in 30-52% yields in two steps. Results: Compound 4d exhibited best inhibitory effect on the formation and growth of chlamydial inclusions. The IC50 value of compound 4d for infectious progenies was 3.55 µM, better than 7.30 µM of CF0001. Conclusion: To find novel anti-chlamydial agents, we have designed and synthesized benzylidene acylhydrazides 4a-4g. Compounds 4a, 4d, 4g showed inhibitory activity on C. muridarum with the IC50 values from 3.55-12 µM. The 3,5-dibromo-4-hydroxyl substitutes on ring B are critical to keep their anti-chlamydial activity. Compound 4d inhibited C. muridarum in a dose-dependent manner without apparent cytotoxicity.

scholarly journals Targeting BMI-1 with PLGA–PEG nanoparticle-containing PTC209 modulates the behavior of human glioblastoma stem cells and cancer cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Elham Poonaki ◽  
Fatemeh Ariakia ◽  
Mohammad Jalili-Nik ◽  
Mehdi Shafiee Ardestani ◽  
Gholamhossein Tondro ◽  
...  
Keyword(s):  
Drug Loading ◽  
Polycomb Group ◽  
Dependent Manner ◽  
Migration Ability ◽  
Jnk Signaling ◽  
Human Glioblastoma ◽  
Core Member ◽  
Ic50 Values ◽  
Human Gbm ◽  
Dose Dependent

AbstractDespite advances in glioblastoma (GBM) treatments, current approaches have failed to improve the overall survival of patients. The oncogene BMI-1, a core member of the polycomb group proteins, is a potential novel therapeutic target for GBM. To enhance the efficacy and reduce the toxicity, PTC209, a BMI-1 inhibitor, was loaded into a PLGA–PEG nanoparticle conjugated with CD133 antibody (Nano-PTC209) and its effect on the behavior of human GBM stem-like cells (GSCs) and the human glioblastoma cell line (U87MG) was assessed. Nano-PTC209 has a diameter of ~ 75 nm with efficient drug loading and controlled release. The IC50 values of Nano-PTC209 for GSCs and U87MG cells were considerably lower than PTC209. Nano-PTC209 significantly decreased the viability of both GSCs and U87MG cells in a dose-dependent manner and caused a significant enhancement of apoptosis and p53 levels as well as inhibition of AKT and JNK signaling pathways. Furthermore, Nano-PTC209 significantly inhibited the migration ability, decreased the activity of metalloproteinase-2 and -9, and increased the generation of reactive oxygen species in both GSCs and U87MG cells. Our data indicate that PLGA–PEG nanoparticle conjugated with CD133 antibody could be an ideal nanocarrier to deliver PTC209 and effectively target BMI-1 for potential approaches in the treatment of GBM.

scholarly journals Antiprotozoan and Antiviral Activities of Non-Cytotoxic Truncated and Variant Analogues of Mussel Defensin

2004 ◽  
Vol 1 (2) ◽  
pp. 167-174 ◽  
Author(s):  
Philippe Roch ◽  
Alain Beschin ◽  
Eric Bernard
Keyword(s):  
Leishmania Major ◽  
Marine Invertebrates ◽  
3D Structure ◽  
Amino Acid Replacement ◽  
Dependent Manner ◽  
Antibacterial And Antifungal Activities ◽  
Mediterranean Mussel ◽  
Antiviral Activities ◽  
Antibacterial And Antifungal ◽  
Dose Dependent

We previously reported the crucial role displayed by loop 3 of defensin isolated from the Mediterranean mussel,Mytilus galloprovincialis, in antibacterial and antifungal activities. We now investigated antiprotozoan and antiviral activities of some previously reported fragments B, D, E, P and Q. Two fragments (D and P) efficiently killedTrypanosoma brucei(ID50 4–12 μM) andLeishmania major(ID50 12–45 μM) in a time/dose-dependent manner. Killing ofT. bruceistarted as early as 1 h after initiation of contact with fragment D and reached 55% mortality after 6 h. Killing was temperature dependent and a temperature of 4°C efficiently impaired the ability to killT. brucei. Fragments bound to the entire external epithelium ofT. brucei. Prevention of HIV-1 infestation was obtained only with fragments P and Q at 20 μM. Even if fragment P was active on both targets, the specificity of fragments D and Q suggest that antiprotozoan and antiviral activities are mediated by different mechanisms. Truncated sequences of mussel defensin, including amino acid replacement to maintain 3D structure and increased positive net charge, also possess antiprotozoan and antiviral capabilities. New alternative and/or complementary antibiotics can be derived from the vast reservoir of natural antimicrobial peptides (AMPs) contained in marine invertebrates.

LUMI-AGGREGOMETER STUDIES OF THE INITIAL ATP-SECRETION FROM COLLAGEN-ADHERENT PLATELETS

1987 ◽  
Author(s):  
R Malmgren
Keyword(s):  
Platelet Adhesion ◽  
Rank Order ◽  
Shape Change ◽  
Dense Granule ◽  
Dependent Manner ◽  
Equal Degree ◽  
Atp Secretion ◽  
Ic50 Values ◽  
Dose Dependent ◽  
Platelet Shape

We have earlier, with the use of a lumi-aggregometer and sub-aggregating doses of collagen (0.2-0.8 ug/ml PRP), been able to detect the initial, aspirin-insensitive secretion of ATP from the collagen-adherent platelets, and to correlate this secretion to the doses of collagen, and onset and degree of subsequent shape change of non-adherent platelets (Malmgren, Thromb Res 4:445, 1986). The present study shows, that 200 ATU of hirudin,which reduced near-maximal aggregation and ATP-secretion induced by high collagen doses (2.5 ug/ml PRP) from 3.35 ± 0.2 uM to 2.85 ± 0.1 uM, did neither reduce the secreted amount of ATP that were 82.5 ± 15 nM in control samples and 90 ± 27.5 nM in hirudin-treated samples, nor reduce platelet shape change when platelets were challenged with 0.31 ug collagen /ml PRP. (200 ATU hirudin completely abolished an equal degree of platelet shape change induced by 0.01 U thrombin). Assuming that 3 % of the platelets in PRP were actually adhering to the collagen fibrils, the secreted amount corresponds to 14.6 ±0.04 pmoles ATP/106adheringplatelets, amounts which closely represented 100 % of their dense granule content. The finding confirms that hirudin does not inhibit platelet adhesion and also indicates, that thrombin-mediated activation of secretory pathways appears not to be involved during the initial phase of platelet-collagen interactions.Dipyridamole (DPA) and dibutyryl cAMP (DBcAMP) inhibited ATP-secretion and platelet aggregation in a dose-dependent manner at high collagen concentrations, but only DBcAMP caused a dose-dependent reduction of ATP secretion (IC50 =10-4 M) induced by sub-aggregating doses of collagen. DPA was devoid of effect in this respect and thus did not inhibit platelet adhesion.Yohimbine, dihydroergotamine and phentolamine reduced ATP-secretion induced by sub-aggregating collagen doses in the mentioned rank order of potency, and with IC50 values in the micromolar range. Ketanserin, ritanserin and propranolol were devoid of effect. The findings suggest that the initial collagen-plate-let interaction involve alfareceptor-mediated mechanisms that may encompass adhesion, while DBcAMP probably interacts with secretory mechanisms connected to phosphatidylinositol turnover.

scholarly journals Cytotoxic, Anti-Migration, and Anti-Invasion Activities on Breast Cancer Cells of Angucycline Glycosides Isolated from a Marine-Derived Streptomyces sp.

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 277 ◽  
Author(s):  
Xin-Ying Qu ◽  
Jin-Wei Ren ◽  
Ai-Hong Peng ◽  
Shi-Qi Lin ◽  
Dan-Dan Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Ring Cleavage ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Streptomyces Sp ◽  
Deoxy Sugar ◽  
Ic50 Values ◽  
Dose Dependent

Four angucycline glycosides were previously characterized from marine-derived Streptomyces sp. OC1610.4. Further investigation of this strain cultured on different fermentation media from that used previously resulted in the isolation of two new angucycline glycosides, vineomycins E and F (1–2), and five known homologues, grincamycin L (3), vineomycinone B2 (4), fridamycin D (5), moromycin B (7), and saquayamycin B1 (8). Vineomycin F (2) contains an unusual ring-cleavage deoxy sugar. All the angucycline glycosides isolated from Streptomyces sp. OC1610.4 were evaluated for their cytotoxic activity against breast cancer cells MCF-7, MDA-MB-231, and BT-474. Moromycin B (7), saquayamycin B1 (8), and saquayamycin B (9) displayed potent anti-proliferation against the tested cell lines, with IC50 values ranging from 0.16 to 0.67 μM. Saquayamycin B (9) inhibited the migration and invasion of MDA-MB-231 cells in a dose-dependent manner, as detected by Transwell and wound-healing assays.

scholarly journals Bersavine: A Novel Bisbenzylisoquinoline Alkaloid with Cytotoxic, Antiproliferative and Apoptosis-Inducing Effects on Human Leukemic Cells

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 964 ◽  
Author(s):  
Darja Koutova ◽  
Monika Kulhava ◽  
Radim Havelek ◽  
Martina Majorosova ◽  
Karel Královec ◽  
...  
Keyword(s):  
Leukemic Cells ◽  
Dependent Manner ◽  
Carcinoma Cell Lines ◽  
Ic50 Values ◽  
Bisbenzylisoquinoline Alkaloid ◽  
Human Leukemic Cells ◽  
Induced Apoptosis ◽  
Dose Dependent ◽  
Increased Activity ◽  
Mcf 7

Bersavine is the new bisbenzylisoquinoline alkaloid isolated from the Berberis vulgaris L. (Berberidaceae) plant. The results of cytotoxicity screening 48 h post-treatment showed that bersavine considerably inhibits the proliferation and viability of leukemic (Jurkat, MOLT-4), colon (HT-29), cervix (HeLa) and breast (MCF-7) cancer cells with IC50 values ranging from 8.1 to 11 µM. The viability and proliferation of leukemic Jurkat and MOLT-4 cells were decreased after bersavine treatment in a time- and dose-dependent manner. Bersavine manifested concentration-dependent antiproliferative activity in human lung, breast, ovarian and hepatocellular carcinoma cell lines using a xCELLigence assay. Significantly higher percentages of MOLT-4 cells exposed to bersavine at 20 µM for 24 h were arrested in the G1 phase of the cell cycle using the flow cytometry method. The higher percentage of apoptotic cells was measured after 24 h of bersavine treatment. The upregulation of p53 phosphorylated on Ser392 was detected during the progression of MOLT-4 cell apoptosis. Mechanistically, bersavine-induced apoptosis is an effect of increased activity of caspases, while reduced proliferation seems dependent on increased Chk1 Ser345 phosphorylation and decreased Rb Ser807/811 phosphorylation in human leukemic cells.

The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3357-3357
Author(s):  
Renate Burger ◽  
Steven Legouill ◽  
Yu-Tzu Tai ◽  
Reshma Shringarpure ◽  
Klaus Podar ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Thymidine Uptake ◽  
Dependent Manner ◽  
Jak Inhibitor ◽  
Synthetic Compound ◽  
Akt Phosphorylation ◽  
Ic50 Values ◽  
Dose Dependent

Abstract In multiple myeloma (MM), IL-6 plays an important role for tumor cell growth, survival, and drug resistance. Janus kinases (JAKs) are protein tyrosine kinases and constitutively associated with the gp130 chain of the IL-6 receptor complex. Their activation is one of the first steps in cytokine receptor-mediated signaling and critical for virtually all subsequent downstream signaling cascades. INCB20 is a small-molecule synthetic compound which, in biochemical assays, potently inhibited all four JAKs with IC50 values between 0.3 nM and 1.2 nM (for comparison, IC50 of AG490, another JAK inhibitor, was >50 μM). Consistent with the central role of JAKs in gp130-mediated signaling, INCB20 inhibited IL-6 induced phosphorylation of SHP-2, STAT1, STAT3, ERK1/2, and AKT in MM1.S cells. In contrast, AKT phosphorylation induced by IGF-1 remained unchanged. Evaluation of the cellular efficacy of INCB20 was performed using the IL-6 dependent INA -6 cell line. Growth of INA-6 cells was inhibited in a dose-dependent manner with an IC50 of approx. 0.5 μM, as measured by [3H]-thymidine uptake and an MTS-based assay (for comparison, the cellular IC50 of AG490 was 15–20 μM). This correlated with an increase in the percentage of apoptotic cells, as evaluated by Apo2.7 staining after 48 hours. Importantly, INA-6 growth was inhibited in the presence of bone marrow stromal cells accompanied by a decrease in phospho-STAT3 levels. Furthermore, in a subcutaneous INA-6-SCID model, INCB20 inhibited tumor growth (and phosphorylated STAT3) in a dose-dependent manner. Our studies provide the conceptual basis for the use of JAK inhibitors as a therapeutic approach in MM.

scholarly journals Synthesis and evaluation of some novel derivatives of 2-propoxybenzylidene isonicotinohydrazide for their potential antimicrobial activity

2012 ◽  
Vol 77 (5) ◽  
pp. 589-597 ◽  
Author(s):  
Manav Malhotra ◽  
Manu Arora ◽  
Abdul Samad ◽  
Kapendra Sahu ◽  
Priyanka Phogat ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Mannich Bases ◽  
Dependent Manner ◽  
Lung Adenocarcinoma Cell Line ◽  
Ic50 Values ◽  
Nmr Methods ◽  
Human Lung Adenocarcinoma Cell ◽  
Dose Dependent ◽  
Derivatives Of

A novel series of Mannich which contained isoniaside were prepared. First by the reaction of 2-propoxybenzaldehyde with isoniazid corresponding hydrazone (2a) was obtained. After that, product 2a after mannich reaction of aminomethylation with formaldehyde and secondary give amines (2b-2k). The inhibitory potencies of the synthesized compounds were assayed in vitro against a panel of microorganisms and against A549 human lung adenocarcinoma cell line. Compounds 2c and 2k displayed moderate to potent antimicrobial activity against all the tested strains and they also exhibited significant cytotoxicity in a dose-dependent manner with an IC50 values ranging from 2.84 to 8.55 (?g) and 0.007-0.030 (?M). The structures of newly synthesized compounds were evaluated by elemental and spectral (IR, 1HNMR, 13C-NMR) methods. The result demonstrates the potential and importance of developing new mannich bases which would be effective against resistant microbial strain and they may be useful leads for anticancer drug development in the future.

scholarly journals Microplastics increase susceptibility of amphibian larvae to the chytrid fungus Batrachochytrium dendrobatidis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaime Bosch ◽  
Barbora Thumsová ◽  
Naiara López-Rojo ◽  
Javier Pérez ◽  
Alberto Alonso ◽  
...  
Keyword(s):  
Batrachochytrium Dendrobatidis ◽  
Dependent Manner ◽  
Chytrid Fungus ◽  
Aquatic Biodiversity ◽  
New Class ◽  
Amphibian Larvae ◽  
Reservoir Species ◽  
Global Concern ◽  
Amphibian Chytrid Fungus ◽  
Dose Dependent

AbstractMicroplastics (MPs), a new class of pollutants that pose a threat to aquatic biodiversity, are of increasing global concern. In tandem, the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) causing the disease chytridiomycosis is emerging worldwide as a major stressor to amphibians. We here assess whether synergies exist between this infectious disease and MP pollution by mimicking natural contact of a highly susceptible species (midwife toads, Alytes obstetricans) with a Bd-infected reservoir species (fire salamanders, Salamandra salamandra) in the presence and absence of MPs. We found that MP ingestion increases the burden of infection by Bd in a dose-dependent manner. However, MPs accumulated to a greater extent in amphibians that were not exposed to Bd, likely due to Bd-damaged tadpole mouthparts interfering with MP ingestion. Our experimental approach showed compelling interactions between two emergent processes, chytridiomycosis and MP pollution, necessitating further research into potential synergies between these biotic and abiotic threats to amphibians.

scholarly journals Synthesis and Broad Antiviral Activity of Novel 2-aryl-isoindolin-1-ones towards Diverse Enterovirus A71 Clinical Isolates

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 985 ◽  
Author(s):  
Yixuan Wang ◽  
Huiqiang Wang ◽  
Xinbei Jiang ◽  
Zhi Jiang ◽  
Tingting Guo ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Viral Disease ◽  
Clinical Isolates ◽  
Dependent Manner ◽  
Potent Antiviral Activity ◽  
Sar Studies ◽  
Enterovirus A71

Enterovirus 71 (EV-A71) is the main causative pathogen of childhood hand, foot and mouth disease. Effective medicine is currently unavailable for the treatment of this viral disease. Using the fragment-hopping strategy, a series of 2-aryl-isoindolin-1-one compounds were designed, synthesized and investigated for their in vitro antiviral activity towards multiple EV-A71 clinical isolates (H, BrCr, Shenzhen98, Jiangsu52) in Vero cell culture in this study. The structure–activity relationship (SAR) studies identified 2-phenyl-isoindolin-1-ones as a new potent chemotype with potent antiviral activity against EV-A71. Ten out of the 24 tested compounds showed significant antiviral activity (EC50 < 10 µM) towards four EV-A71 strains. Compounds A3 and A4 exhibited broad and potent antiviral activity with the 50% effective concentration (EC50) values in the range of 1.23–1.76 μM. Moreover, the selectivity indices of A3 and A4 were significantly higher than those of the reference compound, pirodavir. The western blotting experiment indicated that the viral VP1 was significantly decreased at both the protein and RNA level in a dose-dependent manner following treatment with compound A3. Moreover, compound A3 inhibited the viral replication by acting on the virus entry stage. In summary, this study led to the discovery of 2-aryl-isoindolin-1-ones as a promising scaffold with potent anti-EV-A71 activities, which deserves further in-depth studies.

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