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

K. Brachwitz , B. Voigt , L. Meijer (1) , O. Lozach (1) , C. Schachtele , J. Molnar , A. Hilgeroth

1 MCT - Molécules et cibles thérapeutiques

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.

Mots clés: Animals Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology Aza Compounds/*chemical synthesis/chemistry/pharmacology CDC2 Protein Kinase/*antagonists & inhibitors Drug Resistance; Neoplasm Drug Screening Assays; Antitumor Fluorenes/*chemical synthesis/chemistry/pharmacology Intercalating Agents/*chemical synthesis/chemistry/pharmacology Mice P-Glycoproteins/*metabolism Research Support; Non-U.S. Gov't Structure-Activity Relationship Tumor Cells; Cultured

Domaines: Biochimie, Biologie Moléculaire

K. Brachwitz, B. Voigt, L. Meijer, O. Lozach, C. Schachtele, et al.. Evaluation of the first cytostatically active 1-aza-9-oxafluorenes as novel selective CDK1 inhibitors with P-glycoprotein modulating properties. Journal of Medicinal Chemistry, 2003, 46, pp.876-879. ⟨hal-00020146⟩