Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity

J Med Chem. 1999 Jul 29;42(15):2909-19. doi: 10.1021/jm9900570.


The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure kenpaullone (9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesized. Paullones with different substituents in the 2-, 3-, 4-, 9-, and 11-positions were prepared by a Fischer indole reaction starting from 1H-[1]benzazepine-2,5(3H,4H)-diones 5. Selective substitutions at either the lactam or the indole nitrogen atom were accomplished by treating kenpaullone with alkyl halides in the presence of sodium hydride/THF or potassium hydroxide/acetone, respectively. S-Methylation of the kenpaullone-derived thiolactam 18 yielded the methylthioimidate 19, which gave the hydroxyamidine 20 upon reaction with hydroxylamine. The new paullones were tested both in a CDK1/cyclin B inhibition assay and in the in vitro antitumor cell line-screening program of the National Cancer Institute (NCI). With respect to the CDK1/cyclin B inhibition, electron-withdrawing substituents in the 9-position as well as a 2,3-dimethoxy substitution on the paullone basic scaffold turned out to be favorable. A 9-trifluoromethyl substituent was found to be equivalent to the 9-bromo substituent of kenpaullone. Replacement of the 9-bromo substituent of kenpaullone by a 9-cyano or 9-nitro group produced a substantial increase in enzyme-inhibiting potency. Substitutions in other positions or the replacement of the lactam moiety led to decreased CDK1 inhibition. Noteworthy in vitro antitumor activities (GI(50) values between 1 and 10 microM) were found with the 9-bromo-2,3-dimethoxy-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4t), its 9-trifluoromethyl analogue 4u, the 12-Boc-substituted paullone15, and the methylthioimidate 19, respectively. The 9-nitro-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4j, named alsterpaullone) showed a high CDK1/cyclin B inhibitory activity (IC(50) = 0.035 microM) and exceeded the in vitro antitumor potency of the other paullones by 1 order of magnitude (log GI(50) mean graph midpoint = -6.4 M).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzazepines / chemical synthesis*
  • Benzazepines / chemistry
  • Benzazepines / pharmacology
  • CDC2 Protein Kinase / antagonists & inhibitors*
  • Cyclin B / antagonists & inhibitors*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Starfish
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Benzazepines
  • Cyclin B
  • Enzyme Inhibitors
  • Indoles
  • alsterpaullone
  • CDC2 Protein Kinase