Synthesis, basicity, structural characterization, and biochemical properties of two [(3-hydroxy-4-pyron-2-yl)methyl]amine derivatives showing antineoplastic features

J Org Chem. 2012 Mar 2;77(5):2207-18. doi: 10.1021/jo202270j. Epub 2012 Feb 22.


The N,N'-bis[(3-hydroxy-4-pyron-2-yl)methyl]-N,N'-dimethylethylendiamine (malten) and 4,10-bis[(3-hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (maltonis) were synthesized and characterized. The acid-base behavior, structural characterizations, and biochemical studies in aqueous solution were reported. Each compound contains two 3-hydroxy-2-methyl-4-pyrone units (maltol) symmetrically spaced by a polyamine fragment, the 1,4-dimethylethylendiamine (malten), or the 1,7-dimethyl-1,4,7,10-tetraazacyclododecane (maltonis). They are present at physiological pH 7.4 in the form of differently charged species: neutral but in a zwitterion form for malten and monopositive with an internal separation of charges for maltonis. Malten and maltonis are both able to alter the chromatin structure inducing the covalent binding of genomic DNA with proteins, a feature consistent with the known antiproliferative activity exerted by this class of molecules. Solid-state results and MD simulations in water show that malten, because of its molecular topology, should be more prone than maltonis to act as a donor of H-bonds in intermolecular contacts, thus it should give a better noncovalent approach with the negatively charged DNA. Crystal structures of [H(2)malten](2+) and [H(2)maltonis](2+) cations were also reported.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • DNA / chemistry
  • DNA / drug effects
  • DNA / genetics
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Neoplasm Proteins / chemistry
  • Pyrones / chemical synthesis*
  • Pyrones / chemistry
  • Pyrones / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • U937 Cells


  • 1,7-dimethyl-1,4,7,10-tetraazacyclododecane
  • Antineoplastic Agents
  • Heterocyclic Compounds
  • Neoplasm Proteins
  • Pyrones
  • maltol
  • DNA