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Novel Bipyrazole Targeting Dual CDK-2 and VEGFR-2 Kinases: Synthesis, Anticancer Evaluation, and In Silico Studies

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Abstract

Objective: The objective of the current study was to create a pyrazole scaffold derivation that could be used as a medication to treat specific protein and gene alterations without causing harm to healthy cells. Methods: Focusing on this class of compounds, we report an efficient synthesis of substituted bipyrazole derivative and structural characterizations have been carried out including spectroscopic (FTIR, 1H NMR, 13C NMR, and MS) and physiochemical methods. The newly synthesized derivative was evaluated for their anti-proliferative activity against sixty cancer cell lines at the (NCI/USA) for the one and five-dose assay. Additionally, kinase profiling evaluation was used to screen for further exploration of its putative anticancer pathways. For the target compound, additional ADMET studies were carried out. Results: The acquired data demonstrated a potent effect against nearly the full panel giving GI50 (MG-MID: 3.59 μM). Also, liver of the DENA-rats treated with this product exhibited a remarkable improvement in the hepatic configuration with no marked acute toxicity and normalization of all liver parameters including AST, ALT, and ALP activities and the total bilirubin level. Also, the data indicated that the target compound could exert its cytotxic activity through dual-targeted kinase inhibitory potency against VEGFR-2 and CDK-2/cyclin A2 with (IC50 = 3.37 ± 1.00 and 0.73 ± 0.22 μM, respectively) relating with the references sorafenib and roscovitine (IC50 = 1.60 ± 0.10 and 0.68 ± 1.10 μM, respectively). ADMET studies, demonstrating its good drug-like characteristics and reduced toxicity. Conclusions: This work offers a very effective new molecule that may serve as an excellent starting point for the development of prospective anti-tumor drugs for additional preclinical research.

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DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by regular institutional funding, and no additional grants were obtained.

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Authors and Affiliations

  1. Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, 11754, Cairo, Egypt

    E. S. Nossier, M. M. F. Ismail & H. M. El-Sahrawy

  2. The National Committee of Drugs, Academy of Scientific Research and Technology, 11516, Cairo, Egypt

    E. S. Nossier

  3. Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, El-Behoos Street, Dokki, 12622, Giza, Egypt

    N. M. Khalifa & H. H. Fahmy

  4. Biochemistry Department, Institute of Genetic Engineering and Biotechnology, National Research Centre, El-Behoos Street, Dokki, 12622, Giza, Egypt

    M. M. Ali

Authors
  1. E. S. Nossier
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  2. N. M. Khalifa
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  3. H. H. Fahmy
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  4. M. M. F. Ismail
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  5. H. M. El-Sahrawy
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  6. M. M. Ali
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Contributions

Authors HHF, MMI, and NMK designed the experiments. Authors ESN and MMA synthesized the samples and carried out their biological study. Authors HHF, NMK, and HME participated in data processing and contributed to manuscript preparation. All authors participated in the discussions.

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Correspondence to N. M. Khalifa.

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This article does not contain any studies involving patients or animals as test objects.

Informed consent was not required for this article. No conflict of interest was declared by the authors.

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Nossier, E.S., Khalifa, N.M., Fahmy, H.H. et al. Novel Bipyrazole Targeting Dual CDK-2 and VEGFR-2 Kinases: Synthesis, Anticancer Evaluation, and In Silico Studies. Russ J Bioorg Chem 50, 227–238 (2024). https://doi.org/10.1134/S1068162024010230

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