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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2025-02-01
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| author | Bin Zheng Yi-Xiao Wang Zi-Yan Wu Xin-Wei Li Li-Qing Qin Nan-Ying Chen Gui-Fa Su Jun-Cheng Su Cheng-Xue Pan |
| author_facet | Bin Zheng Yi-Xiao Wang Zi-Yan Wu Xin-Wei Li Li-Qing Qin Nan-Ying Chen Gui-Fa Su Jun-Cheng Su Cheng-Xue Pan |
| author_sort | Bin Zheng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3665bf0b9b5a4468ab7fddd432d012e5 |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj-art-3665bf0b9b5a4468ab7fddd432d012e52025-08-20T03:12:12ZengMDPI AGMolecules1420-30492025-02-0130489410.3390/molecules30040894Design, 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 PathwayBin Zheng0Yi-Xiao Wang1Zi-Yan Wu2Xin-Wei Li3Li-Qing Qin4Nan-Ying Chen5Gui-Fa Su6Jun-Cheng Su7Cheng-Xue Pan8State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaState Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaState Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaState Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaState Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaState Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaState Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaState Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaState Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, ChinaThe 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.https://www.mdpi.com/1420-3049/30/4/894Topo I inhibitor<i>c-MYC</i>PI3K/AKT/NF-κBoral cancerantitumor |
| spellingShingle | Bin Zheng Yi-Xiao Wang Zi-Yan Wu Xin-Wei Li Li-Qing Qin Nan-Ying Chen Gui-Fa Su Jun-Cheng Su Cheng-Xue Pan 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 Molecules Topo I inhibitor <i>c-MYC</i> PI3K/AKT/NF-κB oral cancer antitumor |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Topo I inhibitor <i>c-MYC</i> PI3K/AKT/NF-κB oral cancer antitumor |
| url | https://www.mdpi.com/1420-3049/30/4/894 |
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