New diazaheterocyclylcarbonyl-anthracene derivatives, useful as tubulin polymerization inhibitors for treating benign or malignant tumors

摘要

Diazaheterocyclylcarbonyl-anthracene derivatives (I) are new. Diazaheterocyclylcarbonyl-anthracene derivatives of formula (I) are new. [Image] R, R 1to R 3e.g. hydrogen, 1-8C alkyl, 3-7C cycloalkyl, 1-8C alkylcarbonyl; Z' : oxygen or sulfur; n and m : 0-4; R 4e.g. 1-12C linear or branched alkyl, optionally containing 1-3 double and/or triple bonds, and optionally substituted, or optionally substituted (hetero)aryl or (hetero)aryl(1-4C)alkyl; The diazaheterocyclylcarbonyl group is attached to any of atoms 1-10 of the anthracene. The full definitions are given in the DEFINITIONS (Full Definitions) Field. An independent claim is also included for a method for preparing (I). ACTIVITY : Cytostatic. Cancer cells were incubated for 45 hours with the compound anthracen-9-yl-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]-methanone, then viability determined by measuring dehydrogenase activity with the XTT reagent. The EC50 (mu g/ml) for inhibition of proliferation was 0.047-0.055 for KB/Hela, SKOV3, SF-268, NCI-H460 and RKOP27, but over 3.16 for RKOP27 cells that had been engineered to cause cell-cycle arrest. MECHANISM OF ACTION : Inhibition of tubulin polymerization. The compound anthracen-9-yl-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]-methanone was tested in vitro against lyophilized bovine tubulin, with tubulin polymerization being monitored spectroscopically. The EC50 was 0.85 mu g/ml in presence of 30% associated proteins and 2.52 mu g/ml in absence of these proteins.