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Design, Synthesis and Bioactive Evaluation of Topo I/c-MYC Dual Inhibitors to Inhibit Oral Cancer via Regulating the
Bin Zheng1, Yi-Xiao Wang1, Zi-Yan Wu1
1State 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, China.
Abstract:
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-c]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 7be, 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 7be 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 7be 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 7be exhibited promising anticancer efficacy in vivo, with tumor growth inhibition (TGI) of 64.7% at 20 mg/kg.
Insights
A novel compound, 7be, effectively inhibits oral cancer by targeting DNA topoisomerase I (Topo I) and key signaling pathways. This new pyridothieno[3,2-c]isoquinoline derivative shows significant promise for oral cancer treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Rising oral cancer incidence necessitates novel molecular targets.
- DNA topoisomerase I (Topo I) is a validated target for cancer therapy.
- Selective Topo I inhibitors offer potential for targeted cancer treatment.
Purpose of the Study:
- Design and synthesize novel pyridothieno[3,2-c]isoquinoline 11,11-dioxide derivatives.
- Evaluate the antiproliferative and mechanistic effects of synthesized compounds against oral cancer.
- Investigate the in vivo efficacy of lead compounds in a preclinical oral cancer model.
Main Methods:
- Synthesis of 32 pyridothieno[3,2-c]isoquinoline 11,11-dioxide derivatives.
- Assessment of Topo I inhibition and antiproliferative activity in Cal27 oral cancer cells.
- Molecular docking, Western blotting, apoptosis/autophagy assays, and xenograft studies.
Main Results:
- Compound 7be demonstrated potent Topo I inhibition and significant antiproliferative activity against Cal27 cells.
- 7be suppressed PI3K/AKT/NF-κB signaling, downregulated c-MYC, and inhibited colony formation and migration.
- Molecular docking confirmed 7be's interaction with the Topo I-DNA complex.
- In vivo studies showed 7be achieved 64.7% tumor growth inhibition in a Cal27 xenograft model.
Conclusions:
- The novel pyridothieno[3,2-c]isoquinoline 7be is a potent Topo I inhibitor with significant oral anticancer efficacy.
- 7be targets multiple oncogenic pathways, including PI3K/AKT/NF-κB and c-MYC.
- 7be represents a promising therapeutic candidate for oral cancer treatment.
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