Synthesis, NMR characterization and in vitro antitumor evaluation of new aminophosphonic acid diesters

Eur J Med Chem. 2009 Aug;44(8):3363-7. doi: 10.1016/j.ejmech.2009.03.017. Epub 2009 Mar 24.

Abstract

The synthesis of three novel alpha-aminophosphonic acid diesters N,N-dimethyl-[N'-methyl(diethoxyphosphonyl)-(2-furyl)]-1,3-diaminopropane, p-[N-methyl(diethoxyphosphonyl)-(2-furyl)]toluidine and p-[N-methyl(diethoxyphosphonyl)-(4-dimethylaminophenyl)]toluidine through an addition of diethyl phosphite to N,N-dimethyl-N'-furfurylidene-1,3-diaminopropane, N-furfurylidene-p-toluidine and N-(4-dimethylaminobenzylidene)-p-toluidine, respectively, is reported. The alpha-aminophosphonates have been characterized by elemental analysis, IR and NMR ((1)H, (13)C and (31)P) spectra. The compounds were tested for antiproliferative effects against 4 human leukemic cell lines, namely LAMA-84, K-562 (chronic myeloid leukemias), HL-60 (acute promyelocyte leukemia) and HL-60/Dox (multi-drug-resistant sub-line, characterized by overexpression of MRP-1 (ABC-C1)) and were found to exert concentration-dependent cytotoxic effects. A representative aminophosphonate compound was shown to induce oligonucleosomal DNA fragmentation which implies that the induction of cell death through apoptosis plays an important role for its cytotoxicity mode of action.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design*
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Multidrug Resistance-Associated Proteins / metabolism
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry*
  • Organophosphonates / pharmacology*

Substances

  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • Organophosphonates
  • multidrug resistance-associated protein 1