Design, Synthesis and Bioactive Evaluation of Topo I/<i>c-MYC</i> Dual Inhibitors to Inhibit Oral Cancer via Regulating the PI3K/AKT/NF-κB Signaling Pathway
The significantly rising incidence of oral cancer worldwide urgently requires the identification of novel, effective molecular targets to inhibit the progression of malignancy. DNA topoisomerase I (Topo I) is a well-established target for cancer treatment, and many studies have shown that different...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/4/894 |
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| Summary: | The significantly rising incidence of oral cancer worldwide urgently requires the identification of novel, effective molecular targets to inhibit the progression of malignancy. DNA topoisomerase I (Topo I) is a well-established target for cancer treatment, and many studies have shown that different cancer cell genes could be targeted more selectively with one type of Topo I inhibitor. In this report, a new scaffold pyridothieno[3,2-<i>c</i>]isoquinoline 11,11-dioxide was designed via the combination of the key fragment or bioisoster of Topo I inhibitor azaindenoisoquinolines and G-quadruplex binder quindoline. Thirty-two target derivatives were synthesized, among which compounds <b>7be,</b> with potent Topo I inhibition, exhibited effective antiproliferative activity against Cal27, one of the oral cancer cell lines highly expressing Topo I protein. Further studies indicated that <b>7be</b> could also inhibit the activation of PI3K/AKT/NF-κB pathway and downregulate the level of c-MYC, repress the colony formation and the migration of Cal27 cells and trigger apoptosis and autophagy. Molecular docking indicated that <b>7be</b> could interact with the complex of Topo I and DNA via a mode similar to the indenoisoquinolines. The results of the Cal27 xenograft model confirmed that <b>7be</b> exhibited promising anticancer efficacy in vivo, with tumor growth inhibition (TGI) of 64.7% at 20 mg/kg. |
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| ISSN: | 1420-3049 |