Antitumor agents. 2. Synthesis, structure-activity relationships, and biological evaluation of substituted 5H-pyridophenoxazin-5-ones with potent antiproliferative activity

J Med Chem. 2002 Nov 21;45(24):5217-23. doi: 10.1021/jm020918w.

Abstract

New antiproliferative compounds, 5H-pyrido[3,2-a]phenoxazin-5-ones (1-10), 5H-benzophenoxazin-5-one (11), 5H-pyrido[2,3-a]phenoxazin-5-one (12), 5H-pyrido[3,4-a]phenoxazin-5-one (13), and 5H-pyrido[4,3-a]phenoxazin-5-one (14), were synthesized and evaluated against representative human neoplastic cell lines. The excellent cytotoxic activity of these polycyclic phenoxazinones, structurally related to the actinomycin chromophore, is discussed in terms of structural changes made to rings A and D (Chart 1). Electron-withdrawing or electron-donating substituents were introduced at different positions of ring A to probe the electronic and positional effects of the substitution. A nitro group in R(2) or in R(1) increases the cytotoxic activity, whereas electron-donating methyl groups in any position lead to 10- to 100-fold decreasing of the activity. The low antiproliferative activity of benzophenoxazinone 11 and pyridophenoxazinones 13 and 14 confirms the crucial role of pyridine nitrogen in the W position of ring D in DNA binding. The unexpected high activity exhibited by 12, which has the nitrogen in the X position, could be ascribed to a different mechanism of action, which needs further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Magnetic Resonance Spectroscopy
  • Oxazines / chemical synthesis*
  • Oxazines / chemistry
  • Oxazines / pharmacology
  • Quantum Theory
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Oxazines