Synthesis, Structural Modification, and Antismall Cell Lung Cancer Activity of 3-Arylisoquinolines with Dual Inhibitory Activity on Topoisomerase I and II

Xuemei Deng; Yuying Wang; Xiongqi Yang; Quanwei Yu; Ridong Huang; Hai Chen; Weimin Li; Yang He

doi:10.1021/acs.jmedchem.4c02689

Synthesis, Structural Modification, and Antismall Cell Lung Cancer Activity of 3-Arylisoquinolines with Dual Inhibitory Activity on Topoisomerase I and II

J Med Chem. 2025 Jan 22. doi: 10.1021/acs.jmedchem.4c02689. Online ahead of print.

Authors

Xuemei Deng^{1

2

3

4}, Yuying Wang^{1

2

3

4}, Xiongqi Yang^{1

2

3

4}, Quanwei Yu^{1

2

3

4}, Ridong Huang^{1

2

3

4}, Hai Chen^{1

2

3

4}, Weimin Li^{1

2

3

4}, Yang He^{1

2

3

4}

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
² Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
³ Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
⁴ State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.

PMID: 39844445
DOI: 10.1021/acs.jmedchem.4c02689

Abstract

To overcome the compensatory effect between Topo I and II, one of the reasons accounting for the resistance of SCLC patients, we are pioneering the use of 3-arylisoquinolines to develop dual inhibitors of Topo I/II for the management of SCLC. A total of 46 new compounds were synthesized. Compounds 3g (IC₅₀ = 1.30 μM for NCI-H446 cells and 1.42 μM for NCI-H1048 cells) and 3x (IC₅₀ = 1.32 μM for NCI-H446 cells and 2.45 μM for NCI-H1048 cells) were selected for detailed pharmacological investigation, due to their outstanding cytotoxicity and dual Topo I and II inhibitory activity. 3g and 3x effectively prevent SCLC cell proliferation, invasion, and migration in vitro, byinducing mitochondrial apoptosis and inhibiting the PI3K/Akt/mTOR pathway. Their in vivo tumor inhibition rate is comparable to etoposide with lower toxicity. These results indicated their potential therapeutic values as dual Topo I and II inhibitors for treating SCLC.