Synthesis, molecular docking and anticancer activity of 5,5'-(phenylmethylene)bis(6-amino-2-thiouracil) derivatives

Background: Berberine (BBR), an isoquinoline plant alkaloid isolated from plants such as Coptis chinensis and Hydrastis canadensis, own multiple pharmacological activities. Objective: In this study, seven BBR derivatives were synthesized and their anticancer activity against HeLa cervical and A549 human lung cancer cell lines were evaluated in vitro. Methods: The anti-cancer activity was measured by MTT assay, and apoptosis was demonstrated by the annexin V-FITC/PI staining assay. The intracellular oxidative stress was investigated through DCFH-DA assay. The molecular docking study was carried out in molecular operating environment (MOE). Results: Compound B3 and B5 showed enhanced anti-cancer activity compared with BBR, the IC50 for compound B3 and B5 were significantly lower than BBR, and compound B3 at the concentration of 64 or 128 µM induced apoptosis in HeLa and A549 cell lines. The reactive oxygen species (ROS) was generated in both cell lines when treated with 100 µM of all the compounds, and compound B3 and B5 induced higher activity in the generation of ROS, while compound B3 exhibited the highest activity, these results are in accordance with the cytotoxicity results, indicating the cytotoxicity were mostly generated from the oxidative stress. In addition, molecular docking analysis showed that compound B3 had the greatest affinity with Hsp90. Upon binding, the protective function of Hsp90 was lost, which might explain its higher cytotoxicity from molecular interaction aspect. Conclusion: All the results demonstrated that compound B3 and B5 showed significantly higher anti-cancer ability than BBR, and compound B3 is a promising anticancer drug candidate.

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A New Series of Antileukemic Agents: Design, Synthesis, In Vitro and In Silico Evaluation of Thiazole-Based ABL1 Kinase Inhibitors

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200824100408 ◽

2020 ◽

Vol 20 ◽

Author(s):

Ebru Zeytün ◽

Mehlika D. Altıntop ◽

Belgin Sever ◽

Ahmet Özdemir ◽

Doha E. Ellakwa ◽

...

Keyword(s):

Molecular Docking ◽

Anticancer Activity ◽

Cell Line ◽

Antiproliferative Activity ◽

In Silico ◽

K562 Cell ◽

Kinase Inhibitors ◽

K562 Cell Line ◽

Cytotoxic Effects ◽

Atp Binding Site

Background: After the milestone approval of imatinib, more than 25 antitumor agents targeting kinases have been approved, and several promising candidates are in various stages of clinical evaluation. Objectives : Due to the importance of thiazole scaffold in targeted anticancer drug discovery, the goal of this work is the design of new thiazolyl hydrazones as potent ABL1 kinase inhibitors for the management of chronic myeloid leukemia (CML). Methods: New thiazolyl hydrazones (2a-p) were synthesized and investigated for their cytotoxic effects on K562 CML cell line. Compounds 2h, 2j and 2l showed potent anticancer activity against K562 cell line. The cytotoxic effects of these compounds on other leukemia (HL-60, MT-2 and Jurkat) and HeLa human cervical carcinoma cell lines were also investigated. Furthermore, their cytotoxic effects on mitogen-activated peripheral blood mononuclear cells (MA-PBMCs) were evaluated to determine their selectivity. Due to its selective and potent anticancer activity, compound 2j was benchmarked for its apoptosis-inducing potential on K562 cell line and inhibitory effects on eight different tyrosine kinases (TKs) including ABL1 kinase. In order to investigate the binding mode of compound 2j into the ATP binding site of ABL1 kinase (PDB: 1IEP), molecular docking study was conducted using MOE 2018.01 program. The QikProp module of Schrödinger’s Molecular modelling package was used to predict the pharmacokinetic properties of compounds 2a-p. Results: 4-(4-(Methylsulfonyl)phenyl)-2-[2-((1,3-benzodioxol-4-yl)methylene)hydrazinyl]thiazole (2j) showed antiproliferative activity against K562 cell line with an IC50 value of 8.87±1.93 µM similar to imatinib (IC50= 6.84±1.11 µM). Compound 2j was found to be more effective than imatinib on HL-60, Jurkat and MT-2 cells. Compound 2j also showed cytotoxic activity against HeLa cell line similar to imatinib. The higher selectivity index value of compound 2j than imatinib indicated that its antiproliferative activity was selective. Compound 2j also induced apoptosis in K562 cell line more than imatinib. Among eight TKs, compound 2j showed the strongest inhibitory activity against ABL1 kinase enzyme (IC50= 5.37±1.17 µM). According to molecular docking studies, compound 2j exhibited high affinity to the ATP binding site of ABL1 kinase forming significant intermolecular interactions. On the basis of in silico studies, this compound did not violate Lipinski's rule of five and Jorgensen's rule of three. Conclusion: Compound 2j stands out as a potential orally bioavailable ABL1 kinase inhibitor for the treatment of CML.

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Synthesis, antibacterial activities and molecular docking study of thiouracil derivatives containing oxadiazole moiety

Synthetic Communications ◽

10.1080/00397911.2021.1904990 ◽

2021 ◽

pp. 1-9

Author(s):

Peng-Lei Cui ◽

Di Zhang ◽

Xiu-Min Guo ◽

Shu-Jing Ji ◽

Qing-Mei Jiang

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Antibacterial Activities ◽

Molecular Docking Study ◽

Thiouracil Derivatives

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Anticancer activity of pyrimidodiazepines based on 2-chloro-4-anilinoquinazoline: synthesis, DNA binding and molecular docking

RSC Advances ◽

10.1039/d1ra03509f ◽

2021 ◽

Vol 11 (38) ◽

pp. 23310-23329

Author(s):

Viviana Cuartas ◽

Alberto Aragón-Muriel ◽

Yamil Liscano ◽

Dorian Polo-Cerón ◽

Maria del Pilar Crespo-Ortiz ◽

...

Keyword(s):

Molecular Docking ◽

Dna Binding ◽

Tumor Cell ◽

Anticancer Activity ◽

Cell Lines ◽

Human Tumor ◽

Tumor Cell Lines ◽

Human Tumor Cell ◽

Human Tumor Cell Lines

A new series of quinazoline-based chalcones and pyrimidodiazepines were tested against 60 human tumor cell lines.

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Design, synthesis, molecular docking and ADME studies of novel indole-thiazolidinedione derivatives and their antineoplastic activity as CDK6 inhibitors

New Journal of Chemistry ◽

10.1039/d1nj02808a ◽

2021 ◽

Author(s):

Zeynep Ates-Alagoz ◽

Mehmet Murat Kisla ◽

Fikriye Zengin Karadayi ◽

Sercan Baran ◽

Tuğba Somay Doğan ◽

...

Keyword(s):

Gene Expression ◽

Molecular Docking ◽

Anticancer Activity ◽

Cell Line ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Antineoplastic Activity ◽

Design Synthesis ◽

Mcf 7

Several indole-thiazolidinedione derivatives (9–24) were designed and synthesized as CDK6 inhibitors, and their anticancer activity was probed on the MCF-7 cell line and the effects on gene expression profiles were elucidated.

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