scholarly journals Novel N-Substituted 3-Aryl-4-(Diethoxyphosphoryl)Azetidin-2-Ones as Antibiotic Enhancers and Antiviral Agents in Search for a Successful Treatment of Complex Infections

2021 ◽  
Vol 22 (15) ◽  
pp. 8032
Author(s):  
Iwona E. Głowacka ◽  
Magdalena Grabkowska-Drużyc ◽  
Graciela Andrei ◽  
Dominique Schols ◽  
Robert Snoeck ◽  
...  
Keyword(s):  
Influenza A ◽  
Antiviral Agents ◽  
Coupling Constants ◽  
Dna And Rna ◽  
Cancerous Cell ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Dynamics Simulations ◽  
Cis And Trans ◽  
Human Coronavirus 229E

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl- (diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3–H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC50 in the range 14.5–97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S.aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at β-lactamase, thus protecting the antibiotic from undesirable biotransformation.

Relation between the NMR data and the pseudorotational free-energy profile for oxolane

2019 ◽  
Vol 18 (02) ◽  
pp. 1950012 ◽  
Author(s):  
Wojciech Plazinski ◽  
Karolina Gaweda ◽  
Anita Plazinska
Keyword(s):  
Free Energy ◽  
Quantitative Description ◽  
Coupling Constants ◽  
Biologically Relevant ◽  
Dna And Rna ◽  
Energy Profiles ◽  
Nmr Data ◽  
Biologically Relevant Molecules ◽  
Dynamics Simulations ◽  
Two State Model

The conformation of five-membered furanose rings is a crucial issue for the structural analysis of many biologically-relevant molecules, including DNA and RNA. Oxolane can be treated as a prototypical furanose, composed only of saturated unsubstituted ring. In spite of its structural simplicity, providing the accurate quantitative description of the oxolane conformational features remains a great challenge for both the experimental and theoretical techniques. Here we show the method of recovering the free-energy profiles describing the conformational equilibrium in the oxolane ring (i.e. pseudorotation) based on the experimentally-inferred NMR data ([Formula: see text] coupling constants). The results remain in agreement with the quantum-mechanical-based molecular dynamics simulations and emphasize the large contributions of all ring conformers, even those located at the free-energy barriers. This includes the significant populations of limiting 3T2/2T3 and OE/EO shapes. Our findings provide another example of a poor applicability of the two-state model, which is routinely applied to analyze the NMR data in terms of population of different ring conformers.

scholarly journals Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4014 ◽  
Author(s):  
Dorota G. Piotrowska ◽  
Iwona E. Głowacka ◽  
Dominique Schols ◽  
Robert Snoeck ◽  
Graciela Andrei ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Cytotoxic Activity ◽  
Methyl Acrylate ◽  
Rna Viruses ◽  
Dipolar Cycloaddition ◽  
Dna And Rna ◽  
Cancerous Cell ◽  
Adenocarcinoma Cells ◽  
Ic50 Values ◽  
Hct 116

Homonucleoside analogues cis-16 and trans-17 having a (5-methoxycarbonyl)isoxazolidine framework were synthesized via the 1,3-dipolar cycloaddition of nucleobase-derived nitrones with methyl acrylate. Hydrogenolysis of the isoxazolidines containing thymine, dihydrouracil, theophylline and adenine moieties efficiently led to the formation of the respective γ-lactam analogues. γ-Lactam analogues having 5-bromouracil and 5-chlorouracil fragments were synthesized by treatment of uracil-containing γ-lactams with NBS and NCS. Isoxazolidine and γ-lactam analogues of homonucleosides obtained herein were evaluated for activity against a broad range of DNA and RNA viruses. None of the compounds that were tested exhibited antiviral or cytotoxic activity at concentrations up to 100 µM. The cytostatic activities of all compounds toward nine cancerous cell lines was tested. γ-Lactams trans-15e (Cl-Ura) and cis-15h (Theo) appeared the most active toward pancreatic adenocarcinoma cells (Capan-1), showing IC50 values 21.5 and 18.2 µM, respectively. Isoxazolidine cis-15e (Cl-Ura) inhibited the proliferation of colorectal carcinoma (HCT-116).

scholarly journals Biofabricated Fatty Acids-Capped Silver Nanoparticles as Potential Antibacterial, Antifungal, Antibiofilm and Anticancer Agents

2021 ◽  
Vol 14 (2) ◽  
pp. 139
Author(s):  
Mohammad Azam Ansari ◽  
Sarah Mousa Maadi Asiri ◽  
Mohammad A. Alzohairy ◽  
Mohammad N. Alomary ◽  
Ahmad Almatroudi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Silver Nanoparticles ◽  
Anticancer Agents ◽  
Sem Analysis ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Anticancer Efficacy ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Dose Dependent

The current study demonstrates the synthesis of fatty acids (FAs) capped silver nanoparticles (AgNPs) using aqueous poly-herbal drug Liv52 extract (PLE) as a reducing, dispersing and stabilizing agent. The NPs were characterized by various techniques and used to investigate their potent antibacterial, antibiofilm, antifungal and anticancer activities. GC-MS analysis of PLE shows a total of 37 peaks for a variety of bio-actives compounds. Amongst them, n-hexadecanoic acid (21.95%), linoleic acid (20.45%), oleic acid (18.01%) and stearic acid (13.99%) were found predominately and most likely acted as reducing, stabilizing and encapsulation FAs in LIV-AgNPs formation. FTIR analysis of LIV-AgNPs shows some other functional bio-actives like proteins, sugars and alkenes in the soft PLE corona. The zone of inhibition was 10.0 ± 2.2–18.5 ± 1.0 mm, 10.5 ± 2.5–22.5 ± 1.5 mm and 13.7 ± 1.0–16.5 ± 1.2 against P. aeruginosa, S. aureus and C. albicans, respectively. LIV-AgNPs inhibit biofilm formation in a dose-dependent manner i.e., 54.4 ± 3.1%—10.12 ± 2.3% (S. aureus), 72.7 ± 2.2%–23.3 ± 5.2% (P. aeruginosa) and 85.4 ± 3.3%–25.6 ± 2.2% (C. albicans), and SEM analysis of treated planktonic cells and their biofilm biomass validated the fitness of LIV-AgNPs in future nanoantibiotics. In addition, as prepared FAs rich PLE capped AgNPs have also exhibited significant (p < 0.05 *) antiproliferative activity against cultured HCT-116 cells. Overall, this is a very first demonstration on employment of FAs rich PLE for the synthesis of highly dispersible, stable and uniform sized AgNPs and their antibacterial, antifungal, antibiofilm and anticancer efficacy.

scholarly journals The Antimicrobial, Antioxidant, and Anticancer Activity of Greenly Synthesized Selenium and Zinc Composite Nanoparticles Using Ephedra aphylla Extract

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 470
Author(s):  
Mustafa Mohsen El-Zayat ◽  
Mostafa M. Eraqi ◽  
Hani Alrefai ◽  
Ayman Y. El-Khateeb ◽  
Marwan A. Ibrahim ◽  
...  
Keyword(s):  
Aqueous Extract ◽  
Anticancer Agents ◽  
Antimicrobial Agents ◽  
Selenium Nanoparticles ◽  
Normal Lung ◽  
Zinc Nanoparticles ◽  
Antioxidant Agents ◽  
Hct 116 ◽  
Phytochemical Constituents ◽  
Hct 116 Cells

The current work aimed to synthesize selenium and zinc nanoparticles using the aqueous extract of Ephedra aphylla as a valuable medicinal plant. The prepared nanoparticles were characterized by TEM, zeta potential, and changes in the phytochemical constituents. Hence, the phenolic, flavonoid, and tannin contents were reduced in the case of the prepared samples of nanoparticles than the original values in the aqueous extract. The prepared extract of Ephedra aphylla and its selenium and zinc nanoparticles showed high potency as antioxidant agents as a result of the DPPH• assay. The samples were assessed as anticancer agents against six tumor cells and a normal lung fibroblast (WI-38) cell line. The selenium nanoparticles of Ephedra aphylla extract revealed very strong cytotoxicity against HePG-2 cells (inhibitory concentration (IC50) = 7.56 ± 0.6 µg/mL), HCT-116 cells (IC50 = 10.02 ± 0.9 µg/mL), and HeLa cells (IC50 = 9.23 ± 0.8 µg/mL). The samples were evaluated as antimicrobial agents against bacterial and fungal strains. Thus, selenium nanoparticles showed potent activities against Gram-negative strains (Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli), Gram-positive strains (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus, and Staphylococcus epidermidis), and the fungal strain Candida albicans. In conclusion, the preparation of nanoparticles of either selenium or zinc is crucial for improved biological characteristics.

scholarly journals The structural plasticity of nucleic acid duplexes revealed by WAXS and MD

2021 ◽  
Vol 7 (17) ◽  
pp. eabf6106
Author(s):  
Weiwei He ◽  
Yen-Lin Chen ◽  
Lois Pollack ◽  
Serdal Kirmizialtin
Keyword(s):  
Structural Diversity ◽  
Conformational Ensemble ◽  
Structural Variations ◽  
Dna And Rna ◽  
X Ray Scattering ◽  
Double Stranded Dna ◽  
Binding Partners ◽  
Rna Duplexes ◽  
Dynamics Simulations ◽  
Integrate Solution

Double-stranded DNA (dsDNA) and RNA (dsRNA) helices display an unusual structural diversity. Some structural variations are linked to sequence and may serve as signaling units for protein-binding partners. Therefore, elucidating the mechanisms and factors that modulate these variations is of fundamental importance. While the structural diversity of dsDNA has been extensively studied, similar studies have not been performed for dsRNA. Because of the increasing awareness of RNA’s diverse biological roles, such studies are timely and increasingly important. We integrate solution x-ray scattering at wide angles (WAXS) with all-atom molecular dynamics simulations to explore the conformational ensemble of duplex topologies for different sequences and salt conditions. These tightly coordinated studies identify robust correlations between features in the WAXS profiles and duplex geometry and enable atomic-level insights into the structural diversity of DNA and RNA duplexes. Notably, dsRNA displays a marked sensitivity to the valence and identity of its associated cations.

scholarly journals Design, Syntheses, and Bioevaluations of Some Novel N2-Acryloylbenzohydrazides as Chemostimulants and Cytotoxic Agents

Medicines ◽  
2021 ◽  
Vol 8 (6) ◽  
pp. 27
Author(s):  
Kinjal Lakhani ◽  
Edgar A. Borrego ◽  
Karla G. Cano ◽  
Jonathan R. Dimmock ◽  
Renato J. Aguilera ◽  
...  
Keyword(s):  
Antineoplastic Agent ◽  
Cytotoxic Agents ◽  
Breast Cancer Cell Lines ◽  
Molecular Features ◽  
In Series ◽  
Hct 116 ◽  
Related Series ◽  
Hct 116 Cells ◽  
Related Compounds ◽  
Mcf 7

A series of novel N2-acryloylhydrazides 1a–m and a related series of compounds 6a–c were prepared as potential chemostimulants. In general, these compounds are cytotoxic to human HCT 116 colon cancer cells, as well as human MCF-7 and MDA-MB-231 breast cancer cell lines. A representative compound N1-(3,4-dimethoxyphenylcarbonyl)-N2-acryloylhydrazine 1m sensitized HCT 116 cells to the potent antineoplastic agent 3,5-bis(benzylidene)-4-piperidone 2a, and also to 5-fluorouracil. A series of compounds was prepared that incorporated some of the molecular features of 2a and related compounds with various N2-acryloylhydrazides in series 1. These compounds are potent cytotoxins. Two modes of action of representative compounds are the lowering of mitochondrial membrane potential and increasing the concentration of reactive oxygen species.

scholarly journals Amantadine Inhibits SARS-CoV-2 In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 539
Author(s):  
Klaus Fink ◽  
Andreas Nitsche ◽  
Markus Neumann ◽  
Marica Grossegesse ◽  
Karl-Heinz Eisele ◽  
...  
Keyword(s):  
Influenza A ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Topical Administration ◽  
Counter Measures ◽  
Travel Restrictions ◽  
Drug Treatments ◽  
Intranasal Instillation

Since the SARS-CoV-2 pandemic started in late 2019, the search for protective vaccines and for drug treatments has become mandatory to fight the global health emergency. Travel restrictions, social distancing, and face masks are suitable counter measures, but may not bring the pandemic under control because people will inadvertently or at a certain degree of restriction severity or duration become incompliant with the regulations. Even if vaccines are approved, the need for antiviral agents against SARS-CoV-2 will persist. However, unequivocal evidence for efficacy against SARS-CoV-2 has not been demonstrated for any of the repurposed antiviral drugs so far. Amantadine was approved as an antiviral drug against influenza A, and antiviral activity against SARS-CoV-2 has been reasoned by analogy but without data. We tested the efficacy of amantadine in vitro in Vero E6 cells infected with SARS-CoV-2. Indeed, amantadine inhibited SARS-CoV-2 replication in two separate experiments with IC50 concentrations between 83 and 119 µM. Although these IC50 concentrations are above therapeutic amantadine levels after systemic administration, topical administration by inhalation or intranasal instillation may result in sufficient amantadine concentration in the airway epithelium without high systemic exposure. However, further studies in other models are needed to prove this hypothesis.

scholarly journals TRIM22. A Multitasking Antiviral Factor

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1864
Author(s):  
Isabel Pagani ◽  
Guido Poli ◽  
Elisa Vicenzi
Keyword(s):  
Protein Interactions ◽  
Influenza A ◽  
Direct Interaction ◽  
Type I Interferons ◽  
Viral Gene ◽  
Target Cells ◽  
Type I ◽  
Protein Protein Interactions ◽  
Viral Genomes ◽  
Dna And Rna

Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.

scholarly journals Effects of radiofrequency radiation on colorectal cancer cell proliferation and inflammation

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Elcin Ozgur ◽  
Handan Kayhan ◽  
Gorkem Kismali ◽  
Fatih Senturk ◽  
Merve Sensoz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cell ◽  
Colorectal Cancer Cell ◽  
Radiofrequency Radiation ◽  
Protein Levels ◽  
Intermittent Exposure ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Cell Lines ◽  
Hct 116 ◽  
Hct 116 Cells

Abstract Objectives The aim of this study is to investigate the effects of radiofrequency radiation (RFR) on apoptosis, proliferation, stress response, and inflammation markers in colorectal cancer cells. Methods We tested the effects of intermittent exposure to RFR at different frequencies on two different colorectal cancer cell lines; HCT-116 and DLD-1. Protein levels were subsequently analyzed by ELISA. Results RFR led to a decrease in P53, p-P53, p-P38, and p-IkB levels in HCT-116 cells, while leading to an increase in BAD, p-BAD, p-STAT3,NF-κB levels. Two thousand one hundred Megahertz of RFR altered the P53, BAD, and NF-ΚB expression in HCT-116 cells. P53, p-P53, BAD, p-BAD, NF-κB, p-NF-κB, p-P38, p-SAPK/JNK, p-STAT3, and p-IkB levels increased after exposure to RFR at 900 and 2,100 MHz in DLD-1 cells. Unlike HCT-116 cells, 1,800 MHz of RFR was reported to have no effect on DLD1 cells. Conclusions RFR increased apoptosis and inflammatory response in HCT116 cells, while lowering the active P38 and active P53 levels, which are indicators of poor prognosis in several cancers. Genetic differences, such as P53 mutation (DLD-1), are critical to the cell response to RFR, which explains the reason why scientific studies on the effects of RFR yield contradictory results.

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