Fused aryl-phenazines: scaffold for the development of bioactive molecules

Curr Drug Targets. 2014;15(7):681-8. doi: 10.2174/1389450115666140205152007.

Abstract

Fused aryl phenazine derivatives (benzo[a]phenazine, pyrido[a]phenazine, benzo[a]phenazine diones, tetrahydropyrido[a]phenazine (dermacozines), etc) are important heterocyclic compounds, which exhibit various pharmacological activities, prominently in cancer cell lines. These compounds significantly intercalate between DNA base pairs and inhibit the activities of topoisomerase I and II enzymes (Topo I and II). XR11576, XR5944, NC-190 and NC-182 belong to phenazine/fused aryl phenazine category and are under clinical studies. Several fused aryl phenazine dione compounds such as pyridazino[4,5-b]phenazine-5,12-diones, 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-diones, 6,11-dihydrobenzo[2,3-b]phenazine-6,11-diones, tetrahydropyrido[a]phenazine, etc possessed anticancer activities on various cancer cell lines. Benzo[a]phenazine diimine and various other fused aryl phenazine compounds form coordination complex with the metal ions (Ru, Rh, Zn and Pt) that intercalate with the DNA and are used for the treatment of cancer. These molecules have influence on MDR cancer cells and serve as anticancer agents in MDR cancer cells. The structure activity relationship of the fused aryl phenazine derivatives revealed that the occurrence of four or more nitrogen atoms in the compounds has better anticancer activity than those molecules with less number of nitrogen atoms. Phenazine antibiotics derived from marine microbes are used for the treatment of microbial and worm diseases. Recent patents on these scaffolds showed that the benzo[a]phenazine derivatives have inhibitory activity on topoisomerase enzymes (Topo I and II) and that act as anticancer agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Bacteria / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design*
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Intercalating Agents / chemistry
  • Intercalating Agents / isolation & purification
  • Intercalating Agents / pharmacology*
  • Molecular Structure
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / isolation & purification
  • Organometallic Compounds / pharmacology*
  • Phenazines / chemistry
  • Phenazines / isolation & purification
  • Phenazines / pharmacology*
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / isolation & purification
  • Topoisomerase I Inhibitors / pharmacology*
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / isolation & purification
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Intercalating Agents
  • Organometallic Compounds
  • Phenazines
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors