Evaluation of the first cytostatically active 1-aza-9-oxafluorenes as novel selective CDK1 inhibitors with P-glycoprotein modulating properties

J Med Chem. 2003 Feb 27;46(5):876-9. doi: 10.1021/jm021090g.

Abstract

The first series of synthetic 1-aza-9-oxafluorenes with cytostatic activities in the micromolar range was evaluated as cyclin-dependent kinase (CDK1) inhibitors. Activity was found to be selective in comparison to the inhibition of other kinases within the CDK family. Compounds were shown to inhibit the membrane-efflux pump P-glycoprotein responsible for multidrug resistance in cancer cells. First structure-activity relationships are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • CDC2 Protein Kinase / antagonists & inhibitors*
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Fluorenes / chemical synthesis*
  • Fluorenes / chemistry
  • Fluorenes / pharmacology
  • Intercalating Agents / chemical synthesis*
  • Intercalating Agents / chemistry
  • Intercalating Agents / pharmacology
  • Mice
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents
  • Aza Compounds
  • Fluorenes
  • Intercalating Agents
  • CDC2 Protein Kinase