Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs)

Mohammed, Esraa Zeki; Mahmoud, Walaa R.; George, Riham F.; Hassan, Ghada S.; Omar, Farghaly A.; Georgey, Hanan H.

doi:10.1016/j.bioorg.2021.105347

Cited by 16 publications

(7 citation statements)

References 46 publications

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“…The ability of compounds 7e , 7g , 7k , 7n , and 7o to inhibit the CDK2 enzyme was investigated further (Mohammed et al., 2021). Table 2 shows the IC 50 values.…”

Section: Resultsmentioning

confidence: 99%

“…Appendix A (Supplementary File) contains detailed information about the different biological assays for Cell viability (Mahmoud et al., 2022; Mekheimer et al., 2022), antiproliferative assay (El‐Sheref et al., 2022; Obaid Arhema Frejat et al., 2022), EGFR inhibitory assay (Mohamed et al., 2021), CDK assays (Mohammed et al., 2021) and apoptosis assays (Abou‐Zied et al., 2019; Cory & Adams, 2002; Giaccia & Kastan, 1998; Hisham et al., 2019; Nagata, 1997).…”

Section: Methodsmentioning

confidence: 99%

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New pyrrolidine‐carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors

Frejat,

Zhao,

Furaijit

et al. 2023

Chem Biol Drug Des

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Cancer is one of the leading causes of mortality worldwide, making it a public health concern. A novel series of pyrrolidine‐carboxamide derivatives 7a‐q were developed and examined in a cell viability assay utilizing a human mammary gland epithelial cell line (MCF‐10A), where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Antiproliferative activity was evaluated in vitro against four panels of cancer cell lines A‐549, MCF‐7, Panc‐1, and HT‐29. Compounds 7e, 7g, 7k, 7n, and 7o were the most active as antiproliferative agents capable of triggering apoptosis. Compound 7g was the most potent of all the derivatives, with a mean IC50 of 0.90 μM compared to IC50 of 1.10 μM for doxorubicin. Compound 7g inhibited A‐549 (epithelial cancer cell line), MCF‐7 (breast cancer cell line), and HT‐29 (colon cancer cell line) more efficiently than doxorubicin. EGFR inhibitory assay results of 7e, 7g, 7k, 7n, and 7o demonstrated that the tested compounds inhibited EGFR with IC50 values ranging from 87 to 107 nM in comparison with the reference drug erlotinib (IC50 = 80 nM). 7e, 7g, 7k, 7n, and 7o inhibited CDK2 efficiently in comparison to the reference dinaciclib (IC50 = 20 nM), with IC50 values ranging from 15 to 31 nM. The results of inhibitory activity assay against different CDK isoforms revealed that the tested compounds had preferential inhibitory activity against the CDK2 isoform.

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“…The ability of compounds 7e , 7g , 7k , 7n , and 7o to inhibit the CDK2 enzyme was investigated further (Mohammed et al., 2021). Table 2 shows the IC 50 values.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

New pyrrolidine‐carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors

Frejat,

Zhao,

Furaijit

et al. 2023

Chem Biol Drug Des

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show abstract

“…The inhibition rate can be calculated from the following formulation:

where L sample is the luminescence of the test compound, L blank is the luminescence of the blank, and L kinase is the luminescence of the total kinase. The IC 50 values were regressed according to the inhibition rates of the corresponding 50, 40, 30, 20, and 10 μM concentrations of the test compounds ( Mohammed et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Activity Assays of Cyclin-Dependent Kinase 1 Inhibitors With Flavone Scaffolds

Mou

Deng

et al. 2022

Front. Chem.

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Cyclin-dependent kinase 1 (CDK1) plays an indispensable role in the whole cell cycle. It has become a new target for cancer therapy. According to the binding mode of a pan-CDK inhibitor, flavopiridol with CDK1, and our previous work, a new series of flavone derivatives were discovered. Among them, compound 2a showed the best CDK1 inhibitory and anti-proliferative potencies in the in vitro activity investigation. The IC50 of 2a against CDK1 was 36.42 ± 1.12 μM vs. 11.49 μM ± 0.56 of flavopiridol. In the anti-proliferation activity assays, 2a exhibited better activity toward RAW264.7 than MCF-7 cells. The results indicated that flavone derivatives, besides inhibiting the growth of tumor cells, can also antagonize inflammatory response. Molecular docking results showed that conformation of 2a can form hydrogen bonds and various hydrophobic interactions with the key amino acid residues of CDK1. It can be used as a promising lead compound for CDK1 inhibitor development.

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“…They also showed good potential to interact with the crucial amino acid residues of the CDK target in the performed docking experiments [19]. On the other hand, numerous N-arylpyrazoles have been recently developed and presented good inhibitory activity against certain subtypes of CDKs [23,24]. Among these, 13 and 14 displayed better cytotoxicity than imatinib on MCF-7 breast cancer cell line with IC50 values of 3.0 µM and 4.0 µM, respectively.…”

Section: Introductionmentioning

confidence: 98%

The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro , and in silico mechanistic investigations

Musa

Ihmaid

Hughes

et al. 2023

Journal of Biomolecular Structure and Dynamics

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Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9)Overexpression is associated with a lower overall survival rate in breast cancer patients.Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1 H NMR, 13 C NMR, 13 C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 µM, respectively. Both molecular docking experiments and molecular dynamics simulation were also conducted for further interpretations of the in vitro obtained results.

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Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs)

Cited by 16 publications

References 46 publications

New pyrrolidine‐carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors

New pyrrolidine‐carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors

Design, Synthesis, and Activity Assays of Cyclin-Dependent Kinase 1 Inhibitors With Flavone Scaffolds

The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro , and in silico mechanistic investigations

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