Synthesis and biological evaluation of new asymmetrical bisintercalators as potential antitumor drugs

J Med Chem. 2006 Nov 30;49(24):7198-207. doi: 10.1021/jm0606793.

Abstract

The good results obtained in the past decade with various types of potential bisintercalating agents, e.g., LU 79553, DMP 840, BisBFI, MCI3335, WMC-26, BisAC, BisPA, and the asymmetrical derivative WMC-79 (Chart 1), prompted us to investigate a new series of asymmetrical bisintercalators, compounds 1a-t (Chart 2), which can combine the potentiality of bisintercalation with a possible different mechanism of action due to two diverse chromophores. The DNA-binding properties of these compounds have been examined using fluorometric techniques: target compounds are excellent DNA ligands, with a clear preference for binding to AT-rich duplexes. In vitro cytotoxicity of these derivatives toward human hormone-refractory prostate adenocarcinoma cell line (PC-3) is described. Apoptosis assays of four selected compounds are also reported. Very potent cytotoxic compounds, some of them capable of inducing early apoptosis, have been identified.

MeSH terms

  • Acridines / chemical synthesis*
  • Acridines / chemistry
  • Acridines / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding, Competitive
  • Cell Line, Tumor
  • DNA / chemistry
  • Drug Screening Assays, Antitumor
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Humans
  • Intercalating Agents / chemical synthesis*
  • Intercalating Agents / chemistry
  • Intercalating Agents / pharmacology
  • Male
  • Prostatic Neoplasms
  • Solubility
  • Structure-Activity Relationship

Substances

  • 2-(2-(dimethylamino)ethyl)-6-((3-((3-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benzo(de)isoquinolin-2-yl)propyl)methylamino)propyl)amino)-2,3-dihydro-1H,7H-pyrimido(5,6,1-de)acridine-1,3,7-trione
  • Acridines
  • Antineoplastic Agents
  • Heterocyclic Compounds, 4 or More Rings
  • Intercalating Agents
  • WMC-79
  • DNA