scholarly journals Further evidence for redox activation of the plasmid – dirhenium(III) complexes interactions

2020 ◽  
Keyword(s):  
Dna Cleavage ◽  
Nuclease Activity ◽  
Cluster Compounds ◽  
Organic Radical ◽  
Mobility Shift ◽  
Anticancer Properties ◽  
Dna Cleaving ◽  
Supercoiled Form ◽  
Redox Activation

The DNA-interactions in vitro are still necessary investigations for determination of the possible anticancer properties of the compounds, candidates for application in cancer therapy. The aim of the present work was to realize if the interaction of cis-dicarboxylates of dirhenium(III), with pivalato- (I), isobutirato- (II) and adamanthyl- (III) ligands cleaves the plasmid in the same manner and what is the influence of the ligands on this process. For experiments we used the prokaryotic plasmid which is good model to analyze DNA-cleaving ability of different substances that exists in supercoiled conformation and turns to nicked and linear forms. It was shown that gradual conversion of the supercoiled Form I to a mixture of supercoiled (Form I) and nicked (Form II) DNA takes place and increasing amounts of Form II are produced with higher concentrations of I–III under increasing of concentration that showed the DNA-cleaving abilities of all investigated dirhenium complexes. This process was taking place with different intensity in the range I ˃ II ˃ III, that demonstrates the influence of the organic radical on the cleaving activity of the dirhenium(III) complexes. Under hydrogen peroxide conditions, I and II showed close results, demonstrating more intensive process of cleaving, including formation of the linear plasmid (Form III) under higher concentration, witnessing about redox-activation of the DNA-cleaving reaction. Cleaving activity of III was approximately the same in all experiments, that was demonstrated only by decreasing of the supercoiled form I and increasing of the nicked form II of the plasmid and by absolutely absence of the linear form III of the plasmid. The electrophoresis mobility shift assays showed that rhenium cluster compounds have nuclease activity and confirmed that natural DNA may be their target in the living cells. The conclusion was made that the mechanism of DNA-cleavage reaction of the dirhenium(III) complexes is multiple in which the electron donating (withdrawing) effects of the ligands and catalytic activity of the metal core should be taken in consideration.

scholarly journals A YoeB toxin from A. tumefaciens has metal-dependent DNA cleaving activity

2019 ◽  
Author(s):  
Julia McGillick ◽  
Jessica R. Ames ◽  
Tamiko Murphy ◽  
Eswar Reddem ◽  
Christina R. Bourne
Keyword(s):  
Dna Cleavage ◽  
Potential Role ◽  
Fold Increase ◽  
Nuclease Activity ◽  
Dose Dependence ◽  
Bacterial Cells ◽  
Toxin Concentration ◽  
E Coli ◽  
Dna Cleaving

ABSTRACTToxin-antitoxin (TA) systems, including YoeB-YefM, are important mediators of bacterial physiological changes. Agrobacterium tumefaciens YoeB and YefM are similar to that from E. coli, and interact as a tight heterotetramer with a KD of 653 pM. We have verified that AtYoeB can perform both ribosome-dependent and –independent RNA cleavage. We have also characterized a newly described metal-dependent and pH-sensitive DNA cleaving ability. We note that this DNA cleaving ability is observed at toxin concentrations as low as 150 nM. The dose-dependence of in vitro ribosome-independent RNA and metal-dependent DNA cleavage is equivalent, and requires a ten-fold increase in toxin concentration as opposed to in the presence of the ribosome. The toxin concentration inside bacterial cells is unknown and according to current models, should increase upon activation of YoeB through degradation of the YefM antitoxin. The discovery of general nuclease activity by AtYoeB, and perhaps other YoeB toxins, offers an opportunity to explore the plasticity of this protein fold and its potential role in the evolution of nucleases.

An investigation on the DNA/protein binding, DNA cleavage and in vitro anticancer properties of SNO pincer type palladium(II) complexes with N-substituted isatin thiosemicarbazone ligands

2017 ◽  
Vol 466 ◽  
pp. 61-70 ◽  
Author(s):  
Mathiyan Muralisankar ◽  
Sabeel M. Basheer ◽  
Jebiti Haribabu ◽  
Nattamai S.P. Bhuvanesh ◽  
Ramasamy Karvembu ◽  
...  
Keyword(s):  
Protein Binding ◽  
Dna Cleavage ◽  
Anticancer Properties

scholarly journals Characterization of Argonaute nucleases from mesophilic bacteria Paenibacillus borealis and Brevibacillus laterosporus

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Huarong Dong ◽  
Fei Huang ◽  
Xiang Guo ◽  
Xiaoyi Xu ◽  
Qian Liu ◽  
...  
Keyword(s):  
Small Molecule ◽  
Dna Cleavage ◽  
Low Cost ◽  
Nuclease Activity ◽  
Nucleic Acid Detection ◽  
Mesophilic Bacteria ◽  
Brevibacillus Laterosporus ◽  
Double Stranded Dna ◽  
Small Molecule Detection

AbstractThermophilic Argonaute proteins (Agos) have been shown to utilize small DNA guides for cleaving complementary DNA in vitro, which shows great potential for nucleic acid detection. In this study, we explored mesophilic Agos for the detection of small molecule by cooperating with allosteric transcription factors (aTFs). Two Agos from mesophilic bacteria, Paenibacillus borealis (PbAgo) and Brevibacillus laterosporus (BlAgo), showed nuclease activity for single-stranded DNA at moderate temperatures (37 °C) by using 5′-phosphorylated and 5′-hydroxylated DNA guides. Both Agos perform programmable cleavage of double-stranded DNA, especially in AT-rich regions of plasmid. Furthermore, we developed a simple and low-cost p-hydroxybenzoic acid detection method based on DNA-guided DNA cleavage of Agos and the allosteric effect of HosA, which expands the potential application of small molecule detection by Agos.

scholarly journals The cytotoxic effect of diphtheria toxin on the actin cytoskeleton

2012 ◽  
Vol 17 (1) ◽  
Author(s):  
Başak Varol ◽  
Muhammet Bektaş ◽  
Rüstem Nurten ◽  
Engin Bermek
Keyword(s):  
Actin Cytoskeleton ◽  
Dna Cleavage ◽  
Diphtheria Toxin ◽  
Gel Filtration ◽  
Elongation Factor ◽  
Nuclease Activity ◽  
Entry Rate ◽  
Adp Ribosyltransferase

AbstractDiphtheria toxin (DT) and its N-terminal fragment A (FA) catalyse the transfer of the ADP-ribose moiety of nicotinamide adenine dinucleotide (NAD) into a covalent linkage with eukaryotic elongation factor 2 (eEF2). DT-induced cytotoxicity is versatile, and it includes DNA cleavage and the depolymerisation of actin filaments. The inhibition of the ADP-ribosyltransferase (ADPrT) activity of FA did not affect the deoxyribonuclease activity of FA or its interaction with actin. The toxin entry rate into cells (HUVEC) was determined by measuring the ADP-ribosyltransferase activity. DT uptake was nearly 80% after 30 min. The efficiency was determined as Km = 2.2 nM; Vmax = 0.25 pmol.min−1. The nuclease activity was tested with hyperchromicity experiments, and it was concluded that G-actin has an inhibitory effect on DT nuclease activity. In thepresence of DT and mutant of diphtheria toxin (CRM197), F-actin depolymerisation was determined with gel filtration, WB and fluorescence techniques. In the presence of DT and CRM197, 60–65% F-actin depolymerisation was observed. An in vitro FA-actin interaction and F-actin depolymerisation were reported in our previous paper. The present study thus confirms the depolymerisation of actin cytoskeleton in vivo.

scholarly journals Synthesis, Characterization and Biological Activity of Two New Copper (II) Complexes with N-sulfonamide Ligand

2019 ◽  
Vol 70 (11) ◽  
pp. 4060-4067
Keyword(s):  
Anticancer Agents ◽  
Dna Cleavage ◽  
Antibacterial Properties ◽  
Nuclease Activity ◽  
Normal Fibroblast ◽  
Diffusion Method ◽  
Disk Diffusion Method ◽  
Biological Studies

Despite the fact that a large number of chemotherapeutic anticancer agents have been discovered, cancer still remains a great cause of deaths worldwide. The purpose of our researches is to discover a new antitumor drug. In this aim, two new Cu(II) complexes, (C1) and (C2) with a new ligand, N-(5-trifluoromethyl-<1,3,4>-thiadiazole-2-yl)-benzensulfonamide(HL) were synthesized. The complexes were characterized by elemental analysis, spectral and magnetic determinations. The nuclease activity studies of the complexes confirm their capacity to cleavage the DNA molecule. Both complexes have in vitro antioxidant activity (DPPH, FRAP methods), in vitro (using xanthine /xanthine oxidase system) and in vivo (using S.cerevisiae)SOD mimetic activity.The results of MTT assay on two carcinoma cell lines (HeLa and WM35) indicate that both complexes have antitumor activity, but (C2) has a superior activity compared with (C1) and with Cisplatin. On normal fibroblast (HDFa), (C1) showed toxicity comparable with Cisplatin, but (C2) showed a lower one. Bacterial assays were also performed (by the disk diffusion method) and both complexes have antibacterial activity against S. aureus, E. coli, P. aeroginosa and B. cereus. All the biological studies are in concordance and show that both complexes have biologic activity but (C2)is much more active. Keywords: oxidative DNA cleavage, antioxidant capacity, SOD-mimetic activity, cytotoxicity, antibacterial properties

Vitamin D as potential therapeutic anticancer agent

2018 ◽  
pp. 1-3
Keyword(s):  
Vitamin D ◽  
Anticancer Activity ◽  
Anticancer Agent ◽  
Antitumor Agents ◽  
Metastatic Potential ◽  
Anticancer Properties ◽  
Chemotherapy Agents

The role of vitamin D is implicated in carcinogenesis through numerous biological processes like induction of apoptosis, modulation of immune system inhibition of inflammation and cell proliferation and promotion of cell differentiation. Its use as additional adjuvant drug with cancer treatment may be novel combination for improved outcome of different cancers. Numerous preclinical, epidemiological and clinical studies support the role of vitamin D as an anticancer agent. Anticancer properties of vitamin D have been studied widely (both in vivo and in vitro) among various cancers and found to have promising results. There are considerable data that indicate synergistic potential of calcitriol and antitumor agents. Possible mechanisms for modulatory anticancer activity of vitamin D include its antiproliferative, prodifferentiating, and anti-angiogenic and apoptic properties. Calcitriol reduces invasiveness and metastatic potential of many cancer cells by inhibiting angiogenesis and regulating expression of the key molecules involved in invasion and metastasis. Anticancer activity of vitamin D is synergistic or additive with the antineoplastic actions of several drugs including cytotoxic chemotherapy agents like paclitaxel, docetaxel, platinum base compounds and mitoxantrone. Benefits of addition of vitamin D should be weighed against the risk of its toxicity.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

In Silico Appraisal, Synthesis, Antibacterial Screening and DNA Cleavage for 1,2,5-thiadiazole Derivative

2019 ◽  
Vol 15 (5) ◽  
pp. 445-455 ◽  
Author(s):  
Suraj N. Mali ◽  
Sudhir Sawant ◽  
Hemchandra K. Chaudhari ◽  
Mustapha C. Mandewale
Keyword(s):  
Molecular Docking ◽  
Dna Cleavage ◽  
In Silico ◽  
Oral Absorption ◽  
Inhibition Mechanism ◽  
Hydrogen Binding ◽  
Docking Score ◽  
Antibacterial Screening ◽  
Mycobacteria Tuberculosis

Background: : Thiadiazole not only acts as “hydrogen binding domain” and “two-electron donor system” but also as constrained pharmacophore. Methods:: The maleate salt of 2-((2-hydroxy-3-((4-morpholino-1, 2,5-thiadiazol-3-yl) oxy) propyl) amino)- 2-methylpropan-1-ol (TML-Hydroxy)(4) has been synthesized. This methodology involves preparation of 4-morpholino-1, 2,5-thiadiazol-3-ol by hydroxylation of 4-(4-chloro-1, 2,5-thiadiazol-3-yl) morpholine followed by condensation with 2-(chloromethyl) oxirane to afford 4-(4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol- 3-yl) morpholine. Oxirane ring of this compound was opened by treating with 2-amino-2-methyl propan-1- ol to afford the target compound TML-Hydroxy. Structures of the synthesized compounds have been elucidated by NMR, MASS, FTIR spectroscopy. Results: : The DSC study clearly showed that the compound 4-maleate salt is crystalline in nature. In vitro antibacterial inhibition and little potential for DNA cleavage of the compound 4 were explored. We extended our study to explore the inhibition mechanism by conducting molecular docking, ADMET and molecular dynamics analysis by using Schrödinger. The molecular docking for compound 4 showed better interactions with target 3IVX with docking score of -8.508 kcal/mol with respect to standard ciprofloxacin (docking score= -3.879 kcal/mol). TML-Hydroxy was obtained in silico as non-carcinogenic and non-AMES toxic with good percent human oral absorption profile (69.639%). TML-Hydroxy showed the moderate inhibition against Mycobacteria tuberculosis with MIC 25.00 μg/mL as well as moderate inhibition against S. aureus, Bacillus sps, K. Pneumoniae and E. coli species. Conclusion: : In view of the importance of the 1,2,5-thiadiazole moiety involved, this study would pave the way for future development of more effective analogs for applications in medicinal field.

scholarly journals Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 493
Author(s):  
Dimitrios T. Trafalis ◽  
Sofia Sagredou ◽  
Panayiotis Dalezis ◽  
Maria Voura ◽  
Stella Fountoulaki ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Human Colon ◽  
Tumor Xenograft ◽  
Atp Binding Site ◽  
Anticancer Properties ◽  
Extensive Range ◽  
Dependent Inhibition ◽  
Ht 29

The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time- and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents.

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