Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 3. Structure-activity relationships of fused rings at the 7,8-positions

J Med Chem. 2007 Jun 14;50(12):2858-64. doi: 10.1021/jm070216c. Epub 2007 May 11.

Abstract

As a continuation of our efforts to discover and develop the apoptosis-inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of fused rings at the 7,8-positions. It was found that a five-member aromatic ring, such as pyrrolo with nitrogen at either the 7- or 9-position, is preferred. A six-member aromatic ring, such as benzo or pyrido, also led to potent compounds. The SAR of the 4-aryl group was found to be similar for chromenes with a fused ring at the 7,8-positions. These compounds were found to inhibit tubulin polymerization, indicating that cyclization of the 7,8-positions into a ring does not change the mechanism of action. Compound 2h was identified to be a highly potent apoptosis inducer with an EC50 of 5 nM and a highly potent inhibitor of cell proliferation with a GI50 of 8 nM in T47D cells.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology
  • Caspases / metabolism*
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Enzyme Activation / drug effects
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Structure-Activity Relationship

Substances

  • 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-4,7-dihydropyrano(2,3-e)indole
  • Antineoplastic Agents
  • Benzopyrans
  • Heterocyclic Compounds, 4 or More Rings
  • Indoles
  • Caspases