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

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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A nanocomplex of Cu(II) with theophylline drug; synthesis, characterization, and anticancer activity against K562 cell line

Journal of Molecular Structure ◽

10.1016/j.molstruc.2017.11.029 ◽

2018 ◽

Vol 1155 ◽

pp. 450-456 ◽

Cited By ~ 6

Author(s):

Maryam Sahlabadi ◽

Marzieh Daryanavard ◽

Hassan Hadadzadeh ◽

Zahra Amirghofran

Keyword(s):

Anticancer Activity ◽

Cell Line ◽

K562 Cell ◽

K562 Cell Line ◽

Drug Synthesis

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Synthesis and antiproliferative activity of [2-(phthaloylamino)alkyl]triphenyl phosphonium derivatives against K562 cell line

Anti-Cancer Drugs ◽

10.1097/00001813-200108000-00007 ◽

2001 ◽

Vol 12 (7) ◽

pp. 603-606 ◽

Cited By ~ 2

Author(s):

Florent Ouenadio ◽

Nadia Walchshofer ◽

Chantal Trentesaux ◽

Roland Barret ◽

J Paris

Keyword(s):

Cell Line ◽

Antiproliferative Activity ◽

K562 Cell ◽

K562 Cell Line ◽

Triphenyl Phosphonium

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Comparison of Anticancer Properties of Annona muricata L. Acetonic and Methanolic Leaf Extracts

The Natural Products Journal ◽

10.2174/2210315509666181203125608 ◽

2019 ◽

Vol 9 (4) ◽

pp. 312-320

Author(s):

Jéssica de Castro Nascimento ◽

Rosa Maria do Vale Bosso ◽

Maria Carolina Anholeti ◽

Elaine da Silva Castro ◽

Maximino Alencar Bezerra Junior ◽

...

Keyword(s):

Cell Cycle ◽

Anticancer Activity ◽

Cell Line ◽

K562 Cell ◽

Phase Cell ◽

Annona Muricata ◽

K562 Cell Line ◽

Leaf Extracts ◽

Anticancer Properties ◽

Cytoskeleton Rearrangements

Background: Phytochemical studies of Annona muricata showed the presence of bioactive components with anticancer activity. We compared the anticancer properties of crude acetonic and methanolic A. muricata leaf extracts. Methods: The viabilities of different cell lines (A549, U87, U251, K562 and VERO) treated with A. muricata acetonic or methanolic leaf extracts were measured using the MTT assay. Apoptosis induction, cell cycle and cytoskeleton rearrangements were evaluated in K562 by flow cytometry or fluorescence microscopy. Results: Chemical analyses of the A. muricata extracts showed differences in their composition. The K562 cell line was the most sensitive to the treatment with the acetonic and methanolic extracts, and the IC50 values, respectively were 28.82 (24.41 - 34.69) and 32.49 (27.21 - 40.16) μg/mL. Both extracts induced apoptotic cell death and G0/G1 phase cell cycle arrest. For the first time, cytoskeleton rearrangements were observed in the K562 cell line treated with methanolic extract. Conclusion: These findings suggest that both A. muricata extracts exhibit antileukemic potential and represent a promising source of novel compounds with anticancer activity.

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Molecular Docking, G-QSAR Studies, Synthesis and Anticancer Screening of Some New 2-Phenazinamines as Bcr-Abl Tyrosine Kinase Inhibitors

Current Drug Discovery Technologies ◽

10.2174/1570163815666180913122542 ◽

2020 ◽

Vol 17 (2) ◽

pp. 213-224

Author(s):

Mayura A. Kale ◽

Gajanan M. Sonwane

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Tyrosine Kinase ◽

Anticancer Activity ◽

Cell Line ◽

Kinase Inhibitors ◽

Docking Studies ◽

Abl Tyrosine Kinase ◽

Standard Doxorubicin ◽

Wet Lab

Background: The computational studies on 2-phenazinamines with their protein targets have been carried out to design compounds with potential anticancer activity. This strategy of designing compounds possessing selectivity over specific tyrosine kinase has been achieved through G-QSAR and molecular docking studies. Methods: The objective of this research has been to design newer 2-phenazinamine derivatives as Bcr-Abl tyrosine kinase inhibitors by G-QSAR, molecular docking studies followed by wet lab studies along with evaluation of their anticancer potential. Computational chemistry was done by using VLife MDS 4.3 and Autodock 4.2 followed by wet lab experiments for synthesizing 2- phenazinamine derivatives. The chemical structures of ligands in 2D were drawn by employing Chemdraw 2D Ultra 8.0 and were converted into 3D. These were optimised by using semiempirical method called MOPAC. The protein structure was retrieved from RCSC protein data bank as PDB file. The binding interactions of protein and ligands were done by using PYMOL. The molecular properties of the designed compounds were predicted in silico by using Osiris property explorer. Later, we synthesized novel 13 2-phenazinamine derivatives by treating parent compound with various aldehydes in the presence of dicyclohexylcarbodiimide (DCC) and urea to afford 2-(2-chlorophenyl)-3-(phenazin-2-yl) thiazolidin-4-one and another series of derivatives synthesized with different aldehydes in the presence of p-toluylsulphonic acid, diphydropyridine and benzene sulfonyl chloride to afford benzenesulfonyl-N-(2-chlorobenzyl)-phenazin-2-amine. All the derivatives were tested for invitro anticancer activity on K562 human chronic myelogenous leukemia cell line by employing MTT assay method. Results: The developed G-QSAR models were found to be statistically significant with respect to training (r2=0.8074), cross-validation (q2=0.6521), and external validation (pred_r2=0.5892). The best developed G-QSAR model suggested that the XlogP values of phenazinamine derivatives were found to be highly influential in determining biological activity. The standard drug was found to exhibit binding energy - 6.79 kcal/mol and the derivatives 5b and 6c exhibited binding energy of - 7.46 and - 8.51; respectively. Conclusion: Compounds 5b, 6c were observed to possess good lipophilicity and were found to exhibit better activity than other compounds in the series, although less than standard doxorubicin. The synthesis of these 2-phenazinamine derivatives (5a-m) is reported to be obtained from 2,4- dinitrodiphenylamine by applying appropriate synthetic route. Compounds 5b and 6c showed better cytotoxic activity against K562 cancer cell line when compared to other compounds of the series, although less than standard doxorubicin.

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Molecular Engineering of Curcumin, an Active Constituent of Curcuma longa L. (Turmeric) of the Family Zingiberaceae with Improved Antiproliferative Activity

Plants ◽

10.3390/plants10081559 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1559

Author(s):

Amena Ali ◽

Abuzer Ali ◽

Abu Tahir ◽

Md. Afroz Bakht ◽

Salahuddin ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Molecular Docking ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cell Line ◽

Antiproliferative Activity ◽

Growth Factor Receptor ◽

Molecular Engineering ◽

Curcumin Analogs ◽

Epidermal Growth

Cancer is the world’s second leading cause of death, accounting for nearly 10 million deaths and 19.3 million new cases in 2020. Curcumin analogs are gaining popularity as anticancer agents currently. We reported herein the isolation, molecular engineering, molecular docking, antiproliferative, and anti-epidermal growth factor receptor (anti-EGFR) activities of curcumin analogs. Three curcumin analogs were prepared and docked against the epidermal growth factor receptor (EGFR), revealing efficient binding. Antiproliferative activity against 60 NCI cancer cell lines was assessed using National Cancer Institute (NCI US) protocols. The compound 3b,c demonstrated promising antiproliferative activity in single dose (at 10 µM) as well as five dose (0.01, 0.10, 1.00, 10, and 100 µM). Compound 3c inhibited leukemia cancer panel better than other cancer panels with growth inhibition of 50% (GI50) values ranging from 1.48 to 2.73 µM, and the most promising inhibition with GI50 of 1.25 µM was observed against leukemia cell line SR, while the least inhibition was found against non-small lung cancer cell line NCI-H226 with GI50 value of 7.29 µM. Compounds 3b,c demonstrated superior antiproliferative activity than curcumin and gefitinib. In molecular docking, compound 3c had the most significant interaction with four H-bonds and three π–π stacking, and compound 3c was found to moderately inhibit EGFR. The curcumin analogs discovered in this study have the potential to accelerate the anticancer drug discovery program.

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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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