Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound

Bioorg Med Chem. 2008 Mar 1;16(5):2657-64. doi: 10.1016/j.bmc.2007.11.035. Epub 2007 Nov 17.

Abstract

Diazeniumdiolate anions and their prodrug forms are reliable sources of nitric oxide (NO) that have generated interest as promising therapeutic agents. A number of structural analogues of O(2)-(2,4-dinitro-5-(4-(N-methylamino)benzoyloxy)phenyl) 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), an anti-cancer lead compound that is designed to release NO upon activation by glutathione, were prepared. The nitric oxide release patterns of these O(2)-(2,4-dinitrophenyl) diazeniumdiolates in the presence of glutathione were tested and it was found that in the absence of competing pathways, these compounds release nearly quantitative amounts of NO. The ability of PABA/NO and its structural analogues to inhibit human leukemia cell proliferation was determined and it was found that compounds releasing elevated amounts of NO displayed superior cytotoxic effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • 4-Aminobenzoic Acid / chemical synthesis*
  • 4-Aminobenzoic Acid / chemistry
  • 4-Aminobenzoic Acid / pharmacology*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Survival / drug effects
  • Glutathione / metabolism*
  • HL-60 Cells
  • Humans
  • Leukemia / metabolism*
  • Leukemia / pathology
  • Molecular Structure
  • Nitric Oxide / metabolism*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Structure-Activity Relationship
  • para-Aminobenzoates

Substances

  • Antineoplastic Agents
  • Prodrugs
  • para-Aminobenzoates
  • Nitric Oxide
  • Glutathione
  • 4-Aminobenzoic Acid