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. Epub 2022 May 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase 2
  • HCT116 Cells
  • Humans
  • Molecular Structure
  • Quinolines* / chemistry
  • Quinolines* / pharmacology
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology

Substances

  • Antineoplastic Agents
  • Quinolines
  • Topoisomerase I Inhibitors
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2