Design and synthesis of modified quinolones as antitumoral acridones

J Med Chem. 1999 Jun 17;42(12):2136-44. doi: 10.1021/jm980324m.

Abstract

The bacterial topoisomerase II (DNA gyrase) and the mammalian topoisomerase II represent the cellular targets for quinolone antibacterials and a wide variety of anticancer drugs, respectively. In view of the mechanistic similarities and sequence homologies exhibited by the two enzymes, tentative efforts to selectively shift from an antibacterial to an antitumoral activity was made by synthesizing a series of modified tricyclic quinolones, in which the essential 3-carboxylic function is surrogated by phenolic OH and the classic C-6 fluorine atom is replaced by a NH2 group. The resulting 7-amino-9-acridone derivatives were assayed for their antibacterial as well as cytotoxic activities. No antibacterial activity was found. On the other hand, many derivatives showed significant cytotoxic activity against both HL-60 and P388 leukemias and a wide panel of human and rodent solid tumor cells, derivatives 25 and 26 displaying the best overall antiproliferative activity. Against the LoVo cell line, derivative 25 exhibited higher cytotoxic effects than etoposide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / chemical synthesis*
  • Acridines / chemistry
  • Acridines / pharmacology
  • Animals
  • Anti-Infective Agents / chemical synthesis
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cricetinae
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Mice
  • Quinolones / chemical synthesis*
  • Quinolones / chemistry
  • Quinolones / pharmacology
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors
  • Tumor Cells, Cultured

Substances

  • 7-amino-6-chloro-10-(N,N--diethylaminoethyl)-1,3-dihydroxyacridin-9-one
  • 7-amino-6-chloro-10-(N,N-diethylaminoethyl)-1-hydroxy-3-methoxyacridin-9-one
  • Acridines
  • Anti-Infective Agents
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Quinolones
  • Topoisomerase II Inhibitors