Discovery of novel benzofuro[3,2-b]quinoline derivatives as dual CDK2/Topo I inhibitors

  • Bioorg Chem. 2022 Sep;126:105870. doi: 10.1016/j.bioorg.2022.105870.
Yaoguang Huang  1 ,  Wenwu Liu  1 ,  Shuoqi Huang  2 ,  Deping Li  3 ,  Chang Xu  2 ,  Xiaowen Jiang  4 ,  Mingyue Liu  2 ,  Xin Liu  2 ,  Chengze Zhu  3 ,  Limeng Wu  1 ,  Huanhua Chen  1 ,  Zihua Xu  5 ,  Qingchun Zhao  6
Affiliations
  • 1. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 2. School of Life Sciences, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 3. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 4. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China.
  • 5. Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address: [email protected].
  • 6. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China; School of Life Sciences, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address: [email protected].
PMID: 35636125 DOI: 10.1016/j.bioorg.2022.105870
Abstract

Uncontrolled cell proliferation is a hallmark of Cancer. The major regulator of the cell cycle, cyclin dependent kinase 2 (CDK2), has become a mature target for Cancer treatment. Herein, we describe our efforts toward the discovery of a series of benzofuro[3,2-b]quinoline alkaloid derivatives as CDK2 inhibitors through a scaffold hopping strategy. Compound ZLHQ-5f has Topoisomerase I (Topo I) inhibitory activity due to the unique structure of benzofurano[3,2-b]quinoline. Resultantly, ZLHQ-5f exhibited promising anti-proliferative and CDK2 inhibitory activities. It also arrests the cell cycle in S-phase, triggers Apoptosis in HCT116 cells, and has a good safety profile in vivo. There has yet to be a report on dual CDK2/Topo I Inhibitor, thus this will be a novel attempt.

Keywords
Benzofuro[3,2-b]quinoline alkaloid; CDK2; Cancer; Topo I.
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