Synthesis of 4-aminoguaiazulene and its δ-lactam derivatives

Tricyclic Benzo[cd]azulenes Selectively Inhibit Activities of Pim Kinases and Restrict Growth of Epstein-Barr Virus-Transformed Cells

“…Furthermore, we discovered that the heptafulvenes 1a–e were prone to oxidative cleavage when treated with a mild oxidant m CPBA ( meta -chloroperoxybenzoic acid), yielding the corresponding tricyclic tropones 2a–e (Figure 1 ) [28]. In addition, we have recently described the facile synthesis of tricyclic benzo[ cd ]azulen-3-ones 3a–c , 4a–c and 5 [29], [30] from commercially available guaiazulene. There we had used acid-catalyzed tautomerization reactions to further transform benzo[ cd ]azulen-3-ones 4b–c to regiosiomeric heptafulvenes 1f–g .…”

“…1Prepared according to [28].2Prepared according to [29].3Prepared according to [30].Residual in vitro activity of Pim-1 was determined in the presence of 10 µM concentrations of benzo[ cd ]azulenes dissolved in DMSO. Data were calculated as the percentage of Pim-1 autophosphorylation as compared with DMSO-treated controls.…”

“…Therefore, there is increasing interest towards identification of potent and selective small molecule compounds inhibiting their activity. We have previously described synthesis of tricyclic benzo[ cd ]azulenes [28], [29], [30] and have now recognized that they possess kinase-inhibitory activity. Moreover, we have observed that under in vitro conditions, some of them show striking selectivity against Pim family kinases as compared with the 68 other protein kinases analysed.…”

“…Assays were run at ATP concentrations, which were close to the K m value of each kinase. One concentration (10 µM) of the compounds was used with each kinase with duplicate wells [30]. The data is expressed as the percentage of residual kinase activity.…”

“…Here we have analysed the biological effects of new tricyclic benzo[ cd ]azulenes, the synthesis methodology of some of which we have recently described [28], [29], [30]. We have identified several of them as effective and selective inhibitors against Pim family kinases, and demonstrate that these inhibitors can efficiently interfere with both biochemical and intracellular activities of Pim kinases.…”