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  4. Volume 21, Issue 17
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Volume 21, Issue 17
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

Imatinib, a frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML), was a synthetic tyrosine kinase inhibitor approved by the US Food and Drug Administration.

Objective

To expand the structural diversity of Bcr-Abl inhibitors, we synthesized nine novel imatinib analogues (-) and evaluated their cytostatic effects against human cancer cell lines .

Methods

Imatinib and its analogues were successfully synthesized by an improved method in six main steps. Inhibitory activities of all compounds were evaluated on K562, HL-60, MCF-7, A549 and PBMC . Then, the effect of the most active compound was studied using flow cytometer, real-time qPCR and western blot experiments to determine its mechanism action. Finally, the molecular docking of the most active compound were determined.

Results

The IC of one imatinib analogue (compound ) for K562 and HL-60 was lower than imatinib itself. Further studies indicate that the pro-apoptotic effect of compound on K562 cells was stronger than imatinib over a range of concentrations. Importantly, the real-time qPCR and western blot experiments showed that compound was superior to imatinib in inhibiting Bcr-Abl expression. The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analogue. Introducing benzene (A ring) and piperidine (E ring) rings instead of pyridine (A ring) and piperazine (E ring) in imatinib significantly enhanced the potency of imatinib against K562 and HL-60 cell lines, which is consistent with the docking results.

Conclusion

Imatinib analogue showed a better inhibitory effect on leukemia cell lines than other cell lines, which was consistent with the imatinib-like structure, moreover, had little effect on PBMC. Overall, we conclude that compound has the potential to treat chronic myeloid leukemia.

© 2024 Bentham Science Publishers
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2024-10-01
2025-06-18

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Bcr-Abl Inhibitory Activities of Imatinib Derivatives
Letters in Drug Design & Discovery 21, 4085 (2024); https://doi.org/10.2174/0115701808308483240918115915
/content/journals/lddd/10.2174/0115701808308483240918115915
/content/journals/lddd/10.2174/0115701808308483240918115915
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  • Article Type:     Research Article
Keyword(s): apoptosis; Bcr-Abl; chronic myelogenous leukemia; Imatinib; molecular docking; structure-activity relationship

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