Quinazoline sulfonamide derivatives targeting MicroRNA-34a/MDM4/p53 apoptotic axis with radiosensitizing activity

Abstract

Aim: New quinazoline benzenesulfonamide hybrids 4a–n were synthesized to determine their cytotoxicity and effect on the miR-34a/MDM4/p53 apoptotic pathway. Materials & methods: Cytotoxicity against hepatic, breast, lung and colon cancer cell lines was estimated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results: Compound 4d was the most potent against HepG2 and MCF-7 cancer cells, with potential apoptotic activity verified by a significant upregulation of miR-34a and p53 gene expressions. The apoptotic effect of 4d was further investigated and showed downregulation of miR-21, VEGF, STAT3 and MDM4 gene expression. Conclusion: The anticancer and apoptotic activities of 4d were enhanced post irradiation by a single dose of 8 Gy γ-radiation. Docking analysis demonstrated a valuable affinity of 4d toward VEGFR2 and MDM4 active sites.

Graphical abstract

Summary points

• New quinazoline benzenesulfonamide derivatives were designed and synthesized.

• Cytotoxic activity was measured against MCF-7, HepG2, A549 and Lovo cells.

• Evaluation of the miRNA-34a/MDM4/p53 apoptotic pathway was undertaken to identify the most potent compound.

• Compound 4d induces apoptosis and possesses radiosensitizing activity.

• Molecular docking was performed in the active sites of VEGFR and MDM4.

Keywords: :

• apoptosis
• microRNA
• p53
• quinazoline
• radiosensitizer
• sulfonamide

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Acknowledgments

The authors appreciate the staff members of the γ-irradiation unit at the National Center for Radiation Research and Technology (NCRRT) for carrying out the irradiation process.