scholarly journals Broad-Spectrum Anticancer Activity and Pharmacokinetic Properties of a Prenyloxy-Substituted Indeno[1,2-b]indole Derivative, Discovered as CK2 Inhibitor

2021 ◽  
Vol 14 (6) ◽  
pp. 542
Author(s):  
Ehab El-Awaad ◽  
Robin Birus ◽  
Christelle Marminon ◽  
Zouhair Bouaziz ◽  
Laurens Ballentin ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Broad Spectrum ◽  
Target Engagement ◽  
Anticancer Activities ◽  
Cellular Processes ◽  
Pharmacokinetic Properties ◽  
Substantial Progress ◽  
A Cell ◽  
Kinase Ck2 ◽  
Ck2 Inhibitor

Protein kinase CK2 is involved in regulating cellular processes, such as cell cycle, proliferation, migration, and apoptosis, making it an attractive anticancer target. We previously described a prenyloxy-substituted indeno[1,2-b]indole (5-isopropyl-4-(3-methylbut-2-enyloxy)-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (4p)) as a very potent inhibitor of CK2 holoenzyme (IC50 = 25 nM). Here, we report the broad-spectrum anticancer activity of 4p and provide substantial progress on its pharmacokinetic properties. Using a cell-based CK2 activity assay and live-cell imaging of cultured A431, A549, and LNCaP cancer cell lines, cellular CK2 target engagement was shown as well as strong antiproliferative, anti-migratory and apoptosis-inducing effects of 4p. Furthermore, evidence was found for the ability of 4p to disrupt A549 spheroid cohesion. A series of LC-MS/MS experiments revealed high and rapid cellular uptake (intracellular concentration is approximately 5 µM after 1 h incubation) and low metabolic stability of 4p. These results point to the value of 4p as a potent CK2 inhibitor with promising anticancer activities and should trigger future medicinal chemistry efforts to improve the drug-like properties of this compound.

Anticancer Activity and Topoisomerase II Inhibition of Naphthalimides with ω-Hydroxylalkylamine Side-Chains of Different Lengths

2019 ◽  
Vol 15 (5) ◽  
pp. 550-560
Author(s):  
Mateusz D. Tomczyk ◽  
Anna Byczek-Wyrostek ◽  
Klaudia Strama ◽  
Martyna Wawszków ◽  
Przemysław Kasprzycki ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Topoisomerase Ii ◽  
Significant Activity ◽  
Anticancer Activities ◽  
Human Colon Cancer ◽  
Substitution Pattern ◽  
Topo Ii

Background: The substituted 1,8-Naphthalimides (1H-benzo[de]isoquinoline-1,3(2H)- diones) are known as DNA intercalators stabilizing DNA-Topoisomerase II complexes. This interaction disrupts the cleavage-relegation equilibrium of Topo II, resulting in formation of broken strands of DNA. Objective: To investigate the influence of type of substituents and substitution positions in 1,8- naphthalimde skeleton on the inhibition of Topoisomerase II activity. Methods: The starting 1,8-naphthalimide were prepared from acenaphthene by introduction of appropriate substituents followed by condensation with ω-hydroxylakylamines of different chain length. The substituents were introduced to 1,8-naphthalimide molecule by nucleophilic substitution of leaving groups like nitro or bromo present in 4 or 4,5- positions using the ω- hydroxylalkylamines. The bioactivity of obtained compounds was examined in model cell lines. Results: Antiproliferative activity of selected compounds against HCT 116 human colon cancer cells, human non-small cell lung cells A549 and non-tumorigenic BEAS-2B human bronchial epithelium cells was examined. Several of investigated compounds exhibit a significant activity (IC50 µM to 7 µM) against model cancer cell lines. It was demonstrated that upon treatment with concentration of 200 µM, all derivatives display Topo II inhibitory activity, which may be compared with activity of Amonafide. Conclusion: The replacement of the nitro groups in the chromophore slightly reduces its anticancer activities, whereas the presence of both nitro group and ω-hydroxylalkylamine chain resulted in seriously increased anticancer activity. Obtained compounds showed Topo II inhibitory activity, moreover, influence of the substitution pattern on the ability to inhibit Topo II activity and cancer cells proliferation was observed.

scholarly journals Increases of Lipophilic Antioxidants and Anticancer Activity of Coix Seed Fermented by Monascus purpureus

Foods ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 566
Author(s):  
Haiying Zeng ◽  
Likang Qin ◽  
Xiaoyan Liu ◽  
Song Miao
Keyword(s):  
Anticancer Activity ◽  
Radical Scavenging ◽  
Monascus Purpureus ◽  
Acid Oxidation ◽  
Anticancer Activities ◽  
Lipophilic Extract ◽  
Coix Seed ◽  
Before And After ◽  
Health Promoting ◽  
Human Laryngeal Carcinoma

Lipophilic tocols, γ-oryzanol, and coixenolide in coix seed before and after fermentation by Monascus purpureus were determined. Antioxidant and anticancer activities of raw and fermented coix seed were evaluated using free-radical-scavenging assays and polyunsaturated fatty acid oxidation model, and human laryngeal carcinoma cell HEp2, respectively. Compared to the raw seed, the tocols, γ-oryzanol, and coixenolide contents increased approximately 4, 25, and 2 times, respectively, in the fermented coix seed. Especially, γ-tocotrienol and γ-oryzanol reached 72.5 and 655.0 μg/g in the fermented coix seed. The lipophilic extract from fermented coix seed exhibited higher antioxidant activity in scavenging free radicals and inhibiting lipid oxidation. The inhibitory concentrations for 50% cell survival (IC50) of lipophilic extract from fermented coix seed in inhibiting HEp2 cells decreased by 42%. This study showed that coix seed fermented by M. purpureus increased free and readily bioavailable lipophilic antioxidants and anticancer activity. Therefore, fermentation could enhance the efficacy of the health promoting function of coix seeds.

scholarly journals Integrated genomic analysis reveals regulatory pathways and dynamic landscapes of the tRNA transcriptome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zefang Sun ◽  
Jia Tan ◽  
Minqiong Zhao ◽  
Qiyao Peng ◽  
Mingqing Zhou ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Genomic Analysis ◽  
Rna Seq ◽  
Regulatory Pathways ◽  
Cellular Processes ◽  
Dynamic Landscapes ◽  
Rna Fragments ◽  
A Cell ◽  
Considerable Impact ◽  
New Algorithms

AbstracttRNAs and tRNA-derived RNA fragments (tRFs) play various roles in many cellular processes outside of protein synthesis. However, comprehensive investigations of tRNA/tRF regulation are rare. In this study, we used new algorithms to extensively analyze the publicly available data from 1332 ChIP-Seq and 42 small-RNA-Seq experiments in human cell lines and tissues to investigate the transcriptional and posttranscriptional regulatory mechanisms of tRNAs. We found that histone acetylation, cAMP, and pluripotency pathways play important roles in the regulation of the tRNA gene transcription in a cell-specific manner. Analysis of RNA-Seq data identified 950 high-confidence tRFs, and the results suggested that tRNA pools are dramatically distinct across the samples in terms of expression profiles and tRF composition. The mismatch analysis identified new potential modification sites and specific modification patterns in tRNA families. The results also show that RNA library preparation technologies have a considerable impact on tRNA profiling and need to be optimized in the future.

scholarly journals Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity

2021 ◽  
Author(s):  
Rocío Recio ◽  
Patricia Lerena ◽  
Esther Pozo ◽  
José Manuel Calderón-Montaño ◽  
Estefanía Burgos-Morón ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Broad Spectrum

scholarly journals NBM-HD-1: A Novel Histone Deacetylase Inhibitor with Anticancer Activity

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Wei-Jan Huang ◽  
Yu-Chih Liang ◽  
Shuang-En Chuang ◽  
Li-Ling Chi ◽  
Chi-Yun Lee ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Xenograft Model ◽  
Cyclin B1 ◽  
Dependent Manner ◽  
Cell Cycle Regulators ◽  
Anticancer Activities ◽  
Gene Expressions

HDAC inhibitors (HDACis) have been developed as promising anticancer agents in recent years. In this study, we synthesized and characterized a novel HDACi, termed NBM-HD-1. This agent was derived from the semisynthesis of propolin G, isolated from Taiwanese green propolis (TGP), and was shown to be a potent suppressor of tumor cell growth in human breast cancer cells (MCF-7 and MDA-MB-231) and rat glioma cells (C6), with an IC50ranging from 8.5 to 10.3 μM. Western blot demonstrated that levels of p21(Waf1/Cip1), gelsolin, Ac-histone 4, and Ac-tubulin markedly increased after treatment of cancer cells with NBM-HD-1. After NBM-HD-1 treatment for 1–4 h, p-PTEN and p-AKT levels were markedly decreased. Furthermore, we also found the anticancer activities of NBM-HD-1 in regulating cell cycle regulators. Treatment with NBM-HD-1,p21(Waf1/Cip1)gene expression had markedly increased whilecyclin B1andD1gene expressions had markedly decreased. On the other hand, we found that NBM-HD-1 increased the expressions of tumor-suppressor genep53in a dose-dependent manner. Finally, we showed that NBM-HD-1 exhibited potent antitumor activity in a xenograft model. In conclusion, this study demonstrated that this compound, NBM-HD-1, is a novel and potent HDACi with anticancer activityin vitroandin vivo.

Levofloxacin exerts broad-spectrum anticancer activity via regulation of THBS1, LAPTM5, SRD5A3, MFAP5 and P4HA1

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Xiaoqiong He ◽  
Qian Yao ◽  
Duane D Hall ◽  
Zhongyu Song ◽  
Dan Fan ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Broad Spectrum

Screening ,development of Transglutaminase-2 Inhibitors and its derivative as anti-lung cancer agent by insilico and invitro approach

2021 ◽  
Vol 17 ◽  
Author(s):  
Prachi P. Parvatikar ◽  
Sumangala Patil ◽  
Joy Hoskeri ◽  
Sandeep Swargam ◽  
Raghvendra Kulkarni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transglutaminase 2 ◽  
Docking Studies ◽  
Target Protein ◽  
Cellular Processes ◽  
Cytotoxicity Studies ◽  
Pharmacokinetic Properties ◽  
Cancer Agent ◽  
Inhibition Property ◽  
Cancer Inhibition

Aim: Screening and development of TG2 inhibitors as anti lung cancer agent. Background: Transglutaminase 2 (TG2) is multifunctional and ubiquitously expressed protein from transglutaminase family. It takes part in various cellular processes and plays an important role in the pathogenesis of autoimmune, neurodegerative and also cancer. Background: Transglutaminase 2 (TG2) is multifunctional and ubiquitously expressed protein from transglutaminase family. It takes part in various cellular processes and plays an important role in the pathogenesis of autoimmune, neurodegerative and also cancer. Objective : The of proposed study is to focused on screening of potent inhibitors of TG2 by in-silico method and synthesis its derivative as well as analysis of its activity by invitro approach. Material and Methods: Molecular docking studies have been carried on the different classes of TG2 inhibitors against the target protein. Nearly thirty TG2 inhibitors were selected from literature and docking was performed against transglutaminase 2. The computational ADME property screening was also carried out to check their pharmacokinetic properties. The compounds which exhibited positive ADME properties with good interaction with possessing least binding energy were further validated for their anti-lung cancer inhibition property against A549 cell lines by cytotoxicity studies. Results: The results of present study indicate that the docked complex formed by cystamine showed better binding affinity towards target protein so, this derivative of cystamine is formed using 2,5 dihydrobenzoic acid. Invitro results revealed that both molecule proved good cytotoxic agent against A549 lung cancer (875.10, 553.22 µg/ml) respectively. Further its activity should be validated on TG2 expressing lung cancer. Conclusion : Cystamine and its derivative can be act as potential therapeutic target for lung cancer but further its activity should be validated on TG2 expressing lung cancer.

scholarly journals Chromatin regulates expression of small RNAs to help maintain transposon methylome homeostasis in Arabidopsis

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ranjith K. Papareddy ◽  
Katalin Páldi ◽  
Subramanian Paulraj ◽  
Ping Kao ◽  
Stefan Lutzmayer ◽  
...  
Keyword(s):  
Growth And Development ◽  
Germ Line ◽  
Small Interfering Rnas ◽  
Chromatin States ◽  
Heterochromatin Formation ◽  
Cellular Processes ◽  
A Cell ◽  
Decondensed Chromatin ◽  
And Function ◽  
New Generation

Abstract Background Eukaryotic genomes are partitioned into euchromatic and heterochromatic domains to regulate gene expression and other fundamental cellular processes. However, chromatin is dynamic during growth and development and must be properly re-established after its decondensation. Small interfering RNAs (siRNAs) promote heterochromatin formation, but little is known about how chromatin regulates siRNA expression. Results We demonstrate that thousands of transposable elements (TEs) produce exceptionally high levels of siRNAs in Arabidopsis thaliana embryos. TEs generate siRNAs throughout embryogenesis according to two distinct patterns depending on whether they are located in euchromatic or heterochromatic regions of the genome. siRNA precursors are transcribed in embryos, and siRNAs are required to direct the re-establishment of DNA methylation on TEs from which they are derived in the new generation. Decondensed chromatin also permits the production of 24-nt siRNAs from heterochromatic TEs during post-embryogenesis, and siRNA production from bipartite-classified TEs is controlled by their chromatin states. Conclusions Decondensation of heterochromatin in response to developmental, and perhaps environmental, cues promotes the transcription and function of siRNAs in plants. Our results indicate that chromatin-mediated siRNA transcription provides a cell-autonomous homeostatic control mechanism to help reconstitute pre-existing chromatin states during growth and development including those that ensure silencing of TEs in the future germ line.

scholarly journals Virtual Screening and Statistical Analysis in the Design of New Caffeine Analogues Molecules with Potential Epithelial Anticancer Activity

2018 ◽  
Vol 24 (5) ◽  
pp. 576-594 ◽  
Author(s):  
Josivan da Silva Costa ◽  
Karina da Silva Lopes Costa ◽  
Josiane Viana Cruz ◽  
Ryan da Silva Ramos ◽  
Luciane Barros Silva ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Binding Free Energy ◽  
Inhibitory Effect ◽  
Parametric Models ◽  
World Health ◽  
Pharmacokinetic Properties ◽  
Clinically Significant ◽  
Health Organization

About 132 thousand cases of melanoma (more severe type of skin cancer) were registered in 2014 according to the World Health Organization. This type of cancer significantly affects the quality of life of individuals. Caffeine has shown potential inhibitory effect against epithelial cancer. In this study, it was proposed to obtain new caffeine-based molecules with potential epithelial anticancer activity. For this, a training set of 21 molecules was used for pharmacophore perception procedures. Multiple linear regression analyses were used to propose mono-, bi-, tri-, and tetra-parametric models applied in the prediction of the activity. The generated pharmacophore was used to select 350 molecules available at the ZINCpharmer server, followed by reduction to 24 molecules, after selection using the Tanimoto index, yielding 10 molecules after final selection by predicted activity values > 1.5229. These ten molecules had better pharmacokinetic properties than the other ones used as reference and within the clinically significant limits. Only two molecules show minor hits of toxicity and were submitted to molecular docking procedures, showing BFE (binding free energy) values lower than the reference values. Statistical analyses indicated strong negative correlations between BFE and pharmacophoric properties (high influence on BFE lowering) and practically null correlation between BFE and BBB. The two most promising molecules can be indicated as candidates for further in vitro and in vivo analyzes.

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