Design and synthesis of new spirooxindole candidates and their selenium nanoparticles as potential dual Topo I/II inhibitors, DNA intercalators, and apoptotic inducers

Abstract

A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines. In situ selenium nanoparticles (SeNPs) for some derivatives were synthesised. The targets and the SeNP derivatives were examined for their cytotoxicity towards five cancer cell lines. The inhibitory potencies of the best members against Topo I and Topo II were also assayed besides their DNA intercalation abilities. Compound 7d NPs exhibited the best inhibition against Topo I and Topo II enzymes with IC₅₀ of 0.042 and 1.172 μM, respectively. The ability of compound 7d NPs to arrest the cell cycle and induce apoptosis was investigated. It arrested the cell cycle in the A549 cell at the S phase and prompted apoptosis by 41.02% vs. 23.81% in the control. In silico studies were then performed to study the possible binding interactions between the designed members and the target proteins.

Graphical Abstract

Highlights

• A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines.

• In situ selenium nanoparticles (SeNPs) for some derivatives were synthesised.

• Cytotoxicity, Topo I and Topo II inhibitory assays, and DNA intercalation abilities were evaluated.

• Compound 7d NPs showed the best Topo I and Topo II inhibition.

• Cell cycle arrest, apoptosis induction, and molecular docking studies were performed.

Keywords:

• Molecular hybridisation
• selenium nanoparticles
• dual Topo I/II inhibitors
• cytotoxicity
• apoptosis

Acknowledgements

A.E. expresses his gratitude to the Korea Institute of Science and Technology (KIST) for partially supporting this work through the "2022 KIST School Partnership Project," and he would like to thank the Technology Innovation Commercial Office (TICO) at Mansoura University for their highly effective contribution to the project’s success.

Author contributions

Conceptualisation: Samar El-Kalyoubi and Ahmed A. Al‐Karmalawy; data curation: Samar El-Kalyoubi, Mahmoud T. Abo-Elfadl, Ahmed A. El-Sayed, and Ahmed A. Al-Karmalawy; visualisation: Samar El-Kalyoubi, Mohamed M. Khalifa, Mahmoud T. Abo-Elfadl, Ahmed A. El-Sayed, and Ahmed A. Al-Karmalawy; methodology: Samar El-Kalyoubi, Mahmoud T. Abo-Elfadl, Ahmed A. El-Sayed, and Ahmed A. Al-Karmalawy; validation: Mohamed M. Khalifa and Ahmed A. Al‐Karmalawy; resources and funding: Kyeong Lee and Ahmed Elkamhawy; supervision: Samar El-Kalyoubi and Ahmed A. Al‐Karmalawy; writing – review and editing: Samar El-Kalyoubi, Mohamed M. Khalifa, Mahmoud T. Abo-Elfadl, Ahmed A. El-Sayed, Ahmed Elkamhawy, Kyeong Lee, and Ahmed A. Al-Karmalawy. Finally, all authors revised and approved the final submitted manuscript.

Disclosure statement

The authors declared no conflict of interest.

Additional information

Funding

This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIT) [No. 2018R1A5A2023127] and [No. 2023R1A2C3004599]. This work is also supported by the BK21 FOUR Program, which was funded by the Ministry of Education of Korea through NRF.