A versatile synthesis of novel pan-PIM kinase inhibitors with initial SAR study

Tetrahedron Letters

Volumn 56, Issue 23, 2015, Pages 3186-3190

  Flanders, Yvonne ^a   Dumas, Stephane ^a   Caserta, Justin ^a   Nicewonger, Robb ^b   Baldino, Michael ^a   Lee, Chee Seng ^a   Baldino, Carmen M ^a  

^a Jasco Pharmaceuticals LLC   (United States)

^b EISAI INC   (United States)

Author keywords

Kinase; Multiple myeloma; PIM

Indexed keywords

5 [(2 AMINOPYRIMIDIN 4 YL)METHYLENE]THIAZOLIDINE INHIBITOR; DIAMINE; PHOSPHOTRANSFERASE INHIBITOR; PYRIMIDINE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER CELL LINE; CELL PROLIFERATION ASSAY; CONTROLLED STUDY; NONHUMAN; RAT; SYNTHESIS;

EID: 84929947959     PISSN: 00404039     EISSN: 18733581     Source Type: Journal    
DOI: 10.1016/j.tetlet.2015.01.119     Document Type: Article

References (18)

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15. General displacement procedure: 2 dram round bottomed vials were charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (25 mg, 0.0877 mmol), DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.288 mmol, 3.2 equiv), and the appropriate amine (0.0877 mmol, 1.0 equiv). The reaction mixture was heated to 110 °C and shaken for 24 h. The solvent was removed under reduced pressure (genvac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4). General de-protection procedure: The crude protected products were prepared using the general displacement procedure and were then treated with 2 mL DCE and 500 uL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4).
16. PAMPA assay kit: BD Biosciences Gentest™ pre-coated PAMPA plate system, catalog number 353015. Parallel artificial membrane permeability assays (PAMPA) conditions: The target concentration in the assay was 200 μM, prepared by diluting (50-fold) the 10 mM stock solution of each compound in DMSO into PBS, pH 7.4. The final DMSO concentration was 2%. The 200 μM solutions were added, 300 μL, to wells in the donor plate. The receiver plate, which contained 200 μL of PBS, pH 7.4 per well, was placed in the donor plate and the assembly was incubated for 5 h at ambient temperature. At the end of the incubation period the plates were separated and the compound concentrations in each solution were determined by LC/MS/MS. The assay was performed in triplicate. Dexamethasone and verapamil were used as reference compounds.
17. General reductive amination procedure 1: A 2-dram round bottomed vial was charged with the crude amine/TFA salt intermediate prepared using the general displacement procedure followed by the general TFA de-protection procedure (0.115 mmol), DCE (2 mL), DIPEA (6 equiv 0.690 mmol), DMF (1 mL), the aldehyde (1 equiv, 0.115 mmol), and the reaction mixture was shaken for 1 h at RT. The reaction mixture was then treated with NaBH(OAc)3 (2.5 equiv, 0.230 mmol) and the reaction was shaken 16 h at RT. The reaction mixture was then diluted with DCE (2 mL) and NaHCO3 (2 mL). The aqueous layer was back extracted with DCE (2 × 2 mL) and the combined organic layer was concentrated under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to afford the pure products as the TFA salt.
18. EMD Millipore Kinase Profiler™ Services, www.emdmillipore.com. Assay conditions: Pim-1 (h): Pim-1 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KKRNRTLTV, 10 mM MgAcetate and [γ-33P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 min at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. 10 μL of the reaction is then spotted onto a P30 filtermat and washed three times for 5 min in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. Pim-2 (h): Pim-2 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 300 μM RSRHSSYPAGT, 10 mM MgAcetate and [γ-33P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 min at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. 10 μL of the reaction is then spotted onto a P30 filtermat and washed three times for 5 min in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. Pim-3 (h): Pim-3 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.1% Triton X-100, 300 μM RSRHSSYPAGT, 10 mM MgAcetate and [γ-33P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 min at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. 10 μL of the reaction is then spotted onto a P30 filtermat and washed three times for 5 min in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.