Synthesis and biological evaluation of 4β-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins as topoisomerase-II inhibitors

Bioorg Med Chem Lett. 2018 Jan 15;28(2):71-76. doi: 10.1016/j.bmcl.2017.12.012. Epub 2017 Dec 7.

Abstract

A series of 4β-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents.

Keywords: Cell cycle arrest; DSBs; Podophyllotoxin; Topo-II inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • DNA Topoisomerases, Type II / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Fibroblasts / drug effects
  • Humans
  • Molecular Structure
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Antineoplastic Agents
  • Peptides
  • Topoisomerase II Inhibitors
  • DNA Topoisomerases, Type II