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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively). By contrast, 1e and 4b ON 146040 showed hardly any activity in any of the kinase assays. Here it should be noted that a screen like this gives only preliminary estimates on kinase specificity of the compounds, which is why the results need to be validated by other means. Table 1 Selectivity of benzo[ethoxytropylium fluoroborate [32]) in 45% yield (MeOH, reflux, 2C3 ON 146040 d, Figure 2). This crystalline product has a good chemical stability in aqueous solutions. Since demethylation of the methoxy group on tropones 2a and 2f under standard conditions (BBr3, 2C4 equiv., CH2Cl2, rt, 2C8 h) was found to be unsuccessful, the free phenol analogue 2c (Figure 1 ) [27] was synthesized and subjected to the Knoevenagel condensation (malononitrile, MeOH, reflux, 4 d) to give the phenolic dinitrile 6b (Figure 2). In the presence of hydrazine monohydrate (MeOH, reflux, 20 h), the carbonyl group of 2a was transformed into hydrazide product 7 (Figure 2), which was isolated as an inseparable mixture of two diastereomers (and isomers (NMR, NOE assignment) of oximes 8a (29%, orange needles) and 8b (42%, yellow needles). No ON 146040 2-aminotropone derivatives 9 were isolated as reported previously for the tropone itself to produce a mixture of products under the same reaction conditions [33]. In the presence of phosphonium ylides the ,?-unsaturated ketone moiety of tropone 2a was found to undergo 1,4-conjugate addition reaction instead of the expected Wittig reaction. A related reaction type has ON 146040 been reported previously [34], [35]. The ylide 10 [36] was allowed to react with 2a at low temperature (C78C) to give one main product 11 in 38% yield after aqueous acidic work-up and chromatographic purification. Extensive 2D NMR (HMBC, HSQC, and NOESY) analysis revealed that 11 had an unexpected structure of a quaternary aldehyde with a nonplanar junction between the fused seven and five-membered rings (Figure 2). Catalytic hydrogenation of 2a gave one main product after chromatographic isolation. Instead of reduction of the double bond in the seven member ring system reported for 3,4-fused benztropone [33], it was found that the double bond in the 5-membered ring of 2a was highly susceptible to catalytic hydrogenation, when the reaction conditions were carefully controlled (Figure 2, H2, 10% Pd/C, EtOAc, 0C, 50 min). The racemic non-planar compound 12 was obtained in 40% yield. The C?=?C double-bond in a five-member ring showed regioselectivity towards oxidation, when tropone 2a was treated with FABP5 excess of isomerization of -bonds across the azulene moieties of tricyclic benzo[(HCl, cat., THF, rt, 20 min) and, after deprotonation, derivatized by silylation (NaH, 5 equiv and TBDMSCl 2.5 equiv, rt, 2C3 h) to give 16 in high 84% yield (Figure 2). This allowed the kinase assays with bacterially produced human Pim-1 protein and measured its residual activity in the presence of 10 M concentrations of the compounds. The previously tested compounds 1a, 1e, 2a, 2f, 4b and 4c were used as positive controls to succesfully confirm that the newly obtained results shown in Table 2 were within the same range as those shown in Table 1 . By contrast, ON 146040 the other benzo[and in cell-based assays. activity of Pim-1 was determined in the presence of 10 M concentrations of benzo[kinase activity of Pim-1, in cell-based assays it was far less potent with signs of some cytotoxicity. Indeed, only one of the newly synthesized compounds, 6a, displayed similar properties as 1a and 2f and efficiently impaired the pro-survival advantage of Pim-1 overexpression in FD/Pim44 cells. However, 6a also slightly affected the Neo-expressing control cells at the 5 M concentration. StructureCactivity Relationships of Novel Benzo[activities of compounds used for the structure-activity relationship are given in Figure 1 , Figure 2 and Tables 1 and 2 . In the heptafulvenic compound series with the isopropylidene substituent on the 7-membered ring, 1a with the trifluoromethyl and.

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