Optimization of naphthalimide-imidazoacridone with potent antitumor activity leading to clinical candidate (HKH40A, RTA 502)

J Med Chem. 2007 Nov 15;50(23):5557-60. doi: 10.1021/jm7009777. Epub 2007 Oct 16.

Abstract

Unsymmetrical bifunctional antitumor agent WMC79 was further optimized to generate compound 7b that not only inhibited the growth of many tumor cell lines, but caused rapid apoptosis. Unlike the parent compound, 7b is toxic to both p53 positive and negative cancer cells. It has potent in vivo activity against xenografts of human colon and pancreatic tumors in athymic mice.

Publication types

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

MeSH terms

  • Acridones / chemical synthesis*
  • Acridones / chemistry
  • Acridones / pharmacokinetics
  • Acridones / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • Mice
  • Mice, Nude
  • Naphthalimides / chemical synthesis*
  • Naphthalimides / chemistry
  • Naphthalimides / pharmacokinetics
  • Naphthalimides / pharmacology
  • Neoplasm Transplantation
  • Rats
  • Structure-Activity Relationship
  • Tissue Distribution
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Acridones
  • Antineoplastic Agents
  • Naphthalimides
  • RTA 502
  • TP53 protein, human
  • Tumor Suppressor Protein p53