scholarly journals In Silico Design, Synthesis, and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity

2022 ◽  
Vol 15 (1) ◽  
pp. 82
Author(s):  
Giulia Culletta ◽  
Mario Allegra ◽  
Anna Maria Almerico ◽  
Ignazio Restivo ◽  
Marco Tutone
Keyword(s):  
Cell Line ◽  
Active Site ◽  
Cancer Therapeutics ◽  
Telomerase Activity ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Reverse Transcriptase Enzyme ◽  
Telomerase Inhibitor ◽  
Telomerase Inhibitors ◽  
Promising Target

Telomerase, a reverse transcriptase enzyme involved in DNA synthesis, has a tangible role in tumor progression. Several studies have evidenced telomerase as a promising target for developing cancer therapeutics. The main reason is due to the overexpression of telomerase in cancer cells (85–90%) compared with normal cells where it is almost unexpressed. In this paper, we used a structure-based approach to design potential inhibitors of the telomerase active site. The MYSHAPE (Molecular dYnamics SHared PharmacophorE) approach and docking were used to screen an in-house library of 126 arylsulfonamide derivatives. Promising compounds were synthesized using classical and green methods. Compound 2C revealed an interesting IC50 (33 ± 4 µM) against the K-562 cell line compared with the known telomerase inhibitor BIBR1532 IC50 (208 ± 11 µM) with an SI ~10 compared to the BALB/3-T3 cell line. A 100 ns MD simulation of 2C in the telomerase active site evidenced Phe494 as the key residue as well as in BIBR1532. Each moiety of compound 2C was involved in key interactions with some residues of the active site: Arg557, Ile550, and Gly553. Compound 2C, as an arylsulfonamide derivative, is an interesting hit compound that deserves further investigation in terms of optimization of its structure to obtain more active telomerase inhibitors

scholarly journals The influence of compound itel1296 on telomerase activity and the growth of cancer cells

2011 ◽  
Vol 57 (5) ◽  
pp. 501-510 ◽  
Author(s):  
N.A. Kovalenko ◽  
D.D. Zhdanov ◽  
M.V. Bibikova ◽  
V.Y. Gotovtseva
Keyword(s):  
Cell Line ◽  
Fibroblast Cell ◽  
Telomerase Activity ◽  
Normal Fibroblast ◽  
Tumor Cell Lines ◽  
Sensitive Cell Line ◽  
Telomerase Inhibition ◽  
Telomerase Inhibitor ◽  
Telomerase Inhibitors ◽  
Promising Target

Telomerase is a ribonucleoprotein that synthesizes telomeric repeats and identified as a promising target for anticancer therapy. Here we describe a new compound aITEL1296 as a potent telomerase inhibitor. Its inhibitory activity was a bit higher (IC50 = 0,19±0,02 ng/ml) than that of BIBR1532, one of the most potent telomerase inhibitors known to date. Besides telomerase inhibition aITEL1296 activated apoptotic mechanisms and effectively suppressed proliferation of tumor cell lines (GI50 = 5,0±0,2 ng/ml for most sensitive cell line LnCap) but not normal fibroblast cell line.

scholarly journals Berberine Inhibits Telomerase Activity and Induces Cell Cycle Arrest and Telomere Erosion in Colorectal Cancer Cell Line, HCT 116

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 376
Author(s):  
Muhammad Azizan Samad ◽  
Mohd Zuwairi Saiman ◽  
Nazia Abdul Majid ◽  
Saiful Anuar Karsani ◽  
Jamilah Syafawati Yaacob
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Line ◽  
Cancer Cell ◽  
Telomerase Activity ◽  
Telomerase Inhibitor ◽  
Telomerase Inhibitors ◽  
Hct 116 ◽  
Human Telomerase ◽  
Telomere Erosion

Colorectal cancer (CRC) is the most common cancer among males and females, which is associated with the increment of telomerase level and activity. Some plant-derived compounds are telomerase inhibitors that have the potential to decrease telomerase activity and/or level in various cancer cell lines. Unfortunately, a deeper understanding of the effects of telomerase inhibitor compound(s) on CRC cells is still lacking. Therefore, in this study, the aspects of telomerase inhibitors on a CRC cell line (HCT 116) were investigated. Screening on HCT 116 at 48 h showed that berberine (10.30 ± 0.89 µg/mL) is the most effective (lowest IC50 value) telomerase inhibitor compared to boldine (37.87 ± 3.12 µg/mL) and silymarin (>200 µg/mL). Further analyses exhibited that berberine treatment caused G0/G1 phase arrest at 48 h due to high cyclin D1 (CCND1) and low cyclin-dependent kinase 4 (CDK4) protein and mRNA levels, simultaneous downregulation of human telomerase reverse transcriptase (TERT) mRNA and human telomerase RNA component (TERC) levels, as well as a decrease in the TERT protein level and telomerase activity. The effect of berberine treatment on the cell cycle was time dependent as it resulted in a delayed cell cycle and doubling time by 2.18-fold. Telomerase activity and level was significantly decreased, and telomere erosion followed suit. In summary, our findings suggested that berberine could decrease telomerase activity and level of HCT 116, which in turn inhibits the proliferative ability of the cells.

Design, Synthesis and Biological Evaluation of 1-methyl-1H-pyrazole-5-Carboxamide Derivatives as Novel Anti-Prostate Cancer Agents

2021 ◽  
Vol 21 ◽  
Author(s):  
Xin Chen ◽  
Changqing Xu ◽  
Yuxia Li ◽  
Xiaoming Duan ◽  
Guisen Zhao
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Specific Antigen ◽  
Biological Evaluation ◽  
Castration Resistant Prostate Cancer ◽  
Design Synthesis ◽  
Structural Modifications ◽  
Lead Compounds ◽  
Castration Resistant ◽  
Treat Prostate Cancer

Background: The androgen receptor (AR) signaling functions is a critical driving force for the progression of prostate cancer (PCa) to bring about anti-prostate cancer agents, and AR has been proved to be an effective therapeutic target even for castration-resistant prostate cancer (CRPC). Objective: In order to discover novel anti prostate cancer agents, we performed structural modifications based on the lead compounds T3 and 10e.Methods: A set of 1-methyl- 1H-pyrazole-5-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against both expressions of prostate-specific antigen(PSA) and growth of PCa cell lines. Results: Compound H24 was found to be able to completely block PSA expression at 10 µM, and showed prominent antiproliferative activity in both the LNCaP cell line (GI 50 = 7.73 µM) and PC-3 cell line (GI 50 = 7.07 µM). Conclusions: These preliminary data supported a further evaluation of compound H24 as a potential agent to treat prostate cancer.

scholarly journals Design, synthesis and biological evaluation of 1,2,3-triazole based 2-aminobenzimidazoles as novel inhibitors of LasR dependent quorum sensing in Pseudomonas aeruginosa

RSC Advances ◽  
2019 ◽  
Vol 9 (50) ◽  
pp. 29273-29292 ◽  
Author(s):  
Singireddi Srinivasarao ◽  
Adinarayana Nandikolla ◽  
Shashidhar Nizalapur ◽  
Tsz Tin Yu ◽  
Sravani Pulya ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Cell Line ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Hek 293 ◽  
Line P ◽  
Synthesis And Biological Evaluation ◽  
Hek 293 Cell Line

Out of 40 benzimdazoles, 12 exhibited potent QSI activity against P. aeruginosa6p, most active QSI is docked to LasR and is less toxic against HEK 293 cell line.

scholarly journals Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

2021 ◽  
Author(s):  
Julia Stille ◽  
Jevgenijs Tjutrins ◽  
Guanyu Wang ◽  
Felipe A. Venegas ◽  
Christopher Hennecker ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Antiviral Drugs ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Promising Target ◽  
Starting Point ◽  
Covalent Inhibitors ◽  
Screening Platform ◽  
And Function ◽  
Synthesis And Biological Evaluation

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

scholarly journals Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

2020 ◽  
Author(s):  
Julia Stille ◽  
Jevgenijs Tjutrins ◽  
Guanyu Wang ◽  
Felipe A. Venegas ◽  
Christopher Hennecker ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Antiviral Drugs ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Promising Target ◽  
Starting Point ◽  
Covalent Inhibitors ◽  
Screening Platform ◽  
And Function ◽  
Synthesis And Biological Evaluation

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

Design, synthesis and biological evaluation of cyanopyridines, pyridopyrazolopyrimidines and pyridopyrazolotriazines as potential anticancer agents

2020 ◽  
Vol 17 ◽  
Author(s):  
Reda Mohammed Keshk ◽  
Batoul Mohamed Izzularab
Keyword(s):  
Anticancer Activity ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Biological Evaluation ◽  
Normal Fibroblast ◽  
Cancer Resistance ◽  
Design Synthesis ◽  
Reference Drug ◽  
Chemical Structures

Background: The continuous need for new anticancer drugs is a never-ending task due to cancer resistance to the existing drugs. Objective: This article aimed to Design, synthesis, characterization, and anticancer evaluation of cyanopyridines, pyridopyrazolopyrimidines and pyridopyrazolotriazines. Materials and Methods: FTIR spectra were recorded on Thermo nioclet iso10 FT-IR. 1H and 13C NMR spectra were recorded on on JEOL (500 MHz) and Bruker 400 MHz spectrometer. Anticancer activity was determined using MTT assay against three cancer cell lines namely liver cancer cell line (HepG-2), pancreatic cancer cell line (PANC-1), non-small lung cancer cell line (A-549) and normal fibroblast. Results and Discussion: New series of 3-cyanopyridines (2a,b, 4, 5, 9), pyridopyrimidine (10), pyridopyrazolopyrimidines (11a-c, 12a,b, 18), pyrazolopyridine salt (13) and pyridopyrazolotriazines (16a,b) were synthesized from 3-cyano-4,6- dimethyl-2-pyridone. The novel synthesized compounds were evaluated in vitro for their anticancer activity and their chemical structures were determined by elemental analysis and spectroscopic data. Conclusion: The obtained data revealed that some of the synthesized compounds showed remarkable anticancer activities, especially 11a exhibited superior potency to the reference drug cisplatin against A-549 (IC50 = 9.24 µg mL-1 compared by 11.76 µg mL-1 for reference drug) and safe (IC50 = 66 µg mL-1) for normal fibroblast. Furthermore, compound 16a displayed the highest activity among the tested compounds against HepG-2 (IC50 = 6.45 µg mL-1 equipotent to cisplatin) with the highest safety profile (IC50=113.97 µg mL-1).

scholarly journals Design, synthesis, biological evaluation, and molecular modeling studies of pyrazole-benzofuran hybrids as new α-glucosidase inhibitor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fateme Azimi ◽  
Homa Azizian ◽  
Mohammad Najafi ◽  
Ghadamali Khodarahmi ◽  
Lotfollah Saghaei ◽  
...  
Keyword(s):  
Active Site ◽  
Inhibitory Effect ◽  
Biological Evaluation ◽  
Back Side ◽  
Binding Interaction ◽  
Dynamic Simulations ◽  
Design Synthesis ◽  
Standard Drug ◽  
Molecular Modeling Studies

AbstractIn this work, new derivatives of biphenyl pyrazole-benzofuran hybrids were designed, synthesized and evaluated in vitro through enzymatic assay for inhibitory effect against α-glucosidase activity. Newly identified inhibitors were found to be four to eighteen folds more active with IC50 values in the range of 40.6 ± 0.2–164.3 ± 1.8 µM, as compared to the standard drug acarbose (IC50 = 750.0 ± 10.0 μM). Limited Structure-activity relationship was established. A kinetic binding study indicated that most active compound 8e acted as the competitive inhibitors of α-glucosidase with Ki = 38 μM. Molecular docking has also been performed to find the interaction modes responsible for the desired inhibitory activity. As expected, all pharmacophoric features, used in the design of the hybrid, are involved in the interaction with the active site of the enzyme. In addition, molecular dynamic simulations showed compound 8e oriented vertically into the active site from mouth to the bottom and stabilized the enzyme domains by interacting with the interface of domain A and domain B and the back side of the active site while acarbose formed non-binding interaction with the residue belong to the domain A of the enzyme.

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