, 234-236?C; 1 H-NMR (CDCl 3 ) ? 8.94 (s, 1H, NH), 8.40 (d, J = 9, quinazoline-2-carbimidate (12a): white solid (68 mg, 91%), mp
, 46 (s, 1H, NH), 8.57 (d, J = 8.7 Hz, 1H, H 4 ), 8.54 (s, 1H, quinazoline-2-carbimidate (12b): white solid (56.5 mg, 71%), mp. 196-198?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.7, 1111.
, 45 (s, 1H, NH), 8.59 (s, 1H, mg, 76%), mp. 168-170?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.8, p.1, 1105.
, 45 (s, 1H, NH), 8.73 (s, 1H, H 7 ), 8.55 (d, J = 9, Hz, 1H, H 4 ), 7.93 (d, J = 9.0 Hz, 1H, H 5 )
, 45 (s, 1H, NH), 8.66 (s, 1H, H 7 ), 8.55 (d, J = 8.7 Hz, 1H, H 4 ), 7.91 (d, J = 8.7 Hz, 1H, H 5 )
, 46 (s, 1H, NH), 8.72 (s, 1H, H 7 ), 8.56 (d, J = 8.7 Hz, 1H, H 4 ), 7.93 (d, J = 8.7 Hz, 1H, H 5 ), vol.841, p.1, 1155.
, 45 (s, 1H, NH), 8.73 (s, 1H, H 7 ), quinazoline-2-carbimidate (12g): white powder (78 mg, 92%), mp. 246-248?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.8, p.1, 1078.
, 246-248?C; 1 H-NMR (DMSO-d 6 ) ? 9, mg, 70%), mp
, 46 (s, 1H, NH), 8.57 (s, 1H, H 7 ), 8.56 (d, J = 9, mg, 80%), mp. 178-180?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.826, 1066.
, 41 (s, 1H, NH), 8.56 (s, 1H, H 7 ), 8.52 (d, J = 9, mg, 86%), mp. 190-192?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.3296, p.1, 1065.
, mg, 68%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 9
, quinazoline-2-carbimidate (12l): white solid (74.6 mg, 82%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 9.47 (s, 1H, NH), vol.8, p.61
, mg, 74%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 9
, 44 (s, 1H, NH), 8.62 (s, 1H, mg, 90%), mp. 244-246?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.8, p.716, 1064.
, 60 (s, 1H, NH), 8.56 (d, J = 9.0 Hz, 1H, H 4 ), 8.53 (s, 1H, 7.92 (d, J = 9.0 Hz, 1H, H 5 ), 7.57-7.40 (m, 5H, Ph), 5.48 (s, 2H, CH 2 Ph
, 61 (s, 1H, NH), 8.58 (d, J = 9, 7.93 (d, J = 9.0 Hz, 1H, H 5 ), 7.56-7.38 (m, 5H, Ph), 5.47 (s, 2H, CH 2 Ph, vol.8, p.1, 1105.
, mg, 55%), mp. 168-170?C; 1 H-NMR (DMSO-d 6 ) ? 9.60 (s, 1H, NH), 8.59 (s, 1H, H 7 ), 8.57 (d, J = 9.0 Hz, 1H, H 4 ), 7.93 (d, J = 9.0 Hz, 1H, H 5 ), 7.56-7.39 (m, 5H, Ph), 5.47 (s, 1H, CH 2 Ph, vol.3078, p.837, 1050.
, quinazoline-2-carbimidate (13d): white solid (61 mg, 65%), mp. 212-214?C; 1 H-NMR (DMSO-d 6 ) ? 9.60 (s, 1H, NH), 8.72 (s, 1H, 8.56 (d, J = 8.7 Hz, 1H, H 4 ), 7.93 (d, J = 8.7 Hz, 1H, H 5 ), 7.56-7.38 (m, 5H
, quinazoline-2-carbimidate (13e): white solid (91 mg, 90%), mp. 214-216?C; 1 H-NMR (DMSO-d 6 ) ? 9.58 (s, 1H, NH), 8.65 (s, 1H, H 7 ), 8.55 (d, J = 8.7 Hz, 1H, H 4 ), 7.92 (d, J = 8.7 Hz, 1H, H 5 ), 7.57-7.39 (m, 5H, Ph), 5.47 (s, 2H, CH 2 Ph), 5.13-5.02 (m, 1H, NCH)
, 32 (s, 1H, 7.89 (d, J = 8.7 Hz, 1H, H 5 ), 7.53-7.36 (m, 5H, Ph), 5.50 (s, 2H, CH 2 Ph), 5.16-5.04 (m, 1H, NCH), 2.63 (m, 2H, 2?CH), vol.8, p.1, 1159.
, 27 (s, 1H, quinazoline-2-carbimidate (13g): white solid (59 mg, 94%), mp. 212-214?C; 1 H-NMR (CDCl 3 ) ? 9.11 (s, 1H, NH), 8.42 (d, J = 8.7 Hz, 1H, H 4 ), vol.8, p.744, 1078.
, quinazoline-2-carbimidate (13h): white solid (45 mg, 80%), mp. 190-192?C; 1 H-NMR (DMSO-d 6 ) ? 9.61 (s, 1H, NH), 8.58 (d, J = 9
,
, 248-250?C; 1 H-NMR (CDCl 3 ) ? 8.94 (s, 1H, NH), 8.42 (d, J = 9.0. Hz, 1H, H 4 ), mg, 93%), mp, vol.8
, 36 (br s, 1H, NH), 8.54 (d, J = 9, mg, 76%), mp. 166-168?C, 1 H-NMR (DMSO-d 6 ) ? 9, vol.8
, 37 (s, 1H, NH), 8.59 (s, 1H, mg, 72%), mp. 172-174?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.827, p.1, 1107.
, mg, 80%), mp. 196-198?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.8
, 27 (s, 1H, H 7 ), 7.86 (d, J = 9, 0 Hz, 1H, H 5 ), 5.22 (m, 1H, NCH), 4.49 (q, J = 6.9 Hz, 2H, OCH 2 ), 2.27 (m, 2H, CH), 1.95 (m, 6H, CH), 1.48 (t, J = 6.9 Hz, vol.8, 1055.
, 34 (s, 1H, NH), 8.54 (d, J = 8.7 Hz, 1H, H 4 ), 8.53 (s, 1H, mg, 88%), mp. 228-230?C; 1 H-NMR (DMSO-d 6 ) ? 9
, 174-176?C; 1 H-NMR (DMSO-d 6 ) ? 9.34 (br s, 1H, NH), 8.56 (d, J = 9, mg, 65%), mp, vol.21
, 34 (s, 1H, NH), 8.59 (s, 1H, H 7 ), 8.55 (d, J = 9, quinazoline-2-carboximidate (15c): white solid (81 mg, 90%), mp. 162-164?C; 1 H-NMR (DMSO-d 6 ) ? 9
N-morpholino) propanesulfonic acid (Mops) (pH 7.2), 5 mM EGTA, 15 mM MgCl 2 , 1 mM DTT, 0.1 mM sodium vanadate. 3.3.2. Kinase Preparations and Assays Kinase activities were assayed in triplicates in buffer A or B, for 30 min. at 30?C, at a final adenosine triphosphate (ATP) concentration of 15 µM. Blank values were substracted and activities expressed in % of the maximal activity, i.e., in the absence of inhibitors. Controls were performed with appropriate dilutions of dimethylsulfoxide (DMSO). IC 50 values were calculated from dose-response curves established by Sigma-Plot graphs, EGTA), 1 mM dithiothreitol (DTT), 25 mM Tris-HCl pH 7.5, 50 µg heparin/mL, vol.25 ,
, Its kinase activity was assayed in buffer A, with 1 mg of histone H1/mL, in the presence of 15 µM, CDK5/p25. (Human, recombinant) was prepared as previously described, vol.21
, Ci/mmol; 10 mCi/mL) in a final volume of 30 µL. After 30 min incubation at 30?C, 25 µL aliquots of supernatant were spotted onto sheets of P81 phosphocellulose paper (Whatman) and 20 s later, the filters were washed eight times (for at least 5 min each time) in a solution of 10 mL phosphoric acid/L of water. The wet filters were counted in the presence of 1 mL ACS (Amersham, UK) scintillation fluid. GSK-3?/?. (Porcine brain, native) was assayed, as described for CDK5/p25 but in buffer A and using a GSK-3 specific substrate
Porcine brain, native) was assayed as described for CDK5/p25 but using the CK1-specific peptide substrate RRKHAAIGpSAYSITA, vol.37 ,
coli as a glutathione transferase (GST) fusion protein) was purified by affinity chromatography on glutathione-agarose and assayed, as described for CDK5/p25 using Woodtide (KKISGRLSPIMTEQ) (1.5µg/assay) as a substrate. CLK1. (Human, recombinant, expressed in E. coli as GST fusion protein) was assayed in buffer A (+0.15 mg BSA/mL) with RS ,
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