Synthesis and hypoxic-cytotoxic activity of some 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives

Bioorg Med Chem Lett. 2006 Aug 15;16(16):4209-13. doi: 10.1016/j.bmcl.2006.05.095. Epub 2006 Jun 13.

Abstract

A series of 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives 1 have been synthesized and evaluated for their cytotoxic activity in vitro against human leukemia cell lines: Molt-4, K562, HL60, human liver cancer cell Hep-G2, human prostate cancer cell PC-3 in hypoxia. Most of the compounds showed more potent activity than TPZ. Compounds 1i and 1m displayed encouraging superior activity against Molt-4 and HL-60 cell lines. Three potential derivatives received the test of the activity in hypoxia and in normoxia against Molt-4 and HL-60 cell lines and showed obvious hypoxia selectivity. Further mechanism study revealed that the cytotoxic activities of compounds 1i and 1k in Molt-4 cells might be mediated by modulation of p53 protein expression and mitochondrial membrane potential (DeltaPsi(m)).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • HL-60 Cells
  • Humans
  • Hypoxia*
  • Inhibitory Concentration 50
  • K562 Cells
  • Membrane Potentials
  • Models, Chemical
  • Tirapazamine
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Triazines
  • Tumor Suppressor Protein p53
  • Tirapazamine