Conclusions A series of novel sulfamide and triazole benzodiazepines inhibitors of p53-MDM2 protein-protein interaction were successfully obtained by the principle of bioisosterism

Conclusions A series of novel sulfamide and triazole benzodiazepines inhibitors of p53-MDM2 protein-protein interaction were successfully obtained by the principle of bioisosterism. antiproliferative activity of the designed p53-MDM2 inhibitors, four human tumor cell lines, namely U-2 OS (wild-type p53), A549 (wild-type p53), Saos-2 (p53 null), and NCI-H1299 (p53 null), were chosen for assaying. Nutlin-3 was used as a reference compound. The Roflumilast N-oxide obtained antitumor activity, potentially due to their poor aqueous solubility. Comparing with the totally inactive sulfamide benzodiazepines, the triazole benzodiazepines showed promising antiproliferative activity. Notably, compound 16 showed better Roflumilast N-oxide activity (values) are given in ppm and Hz, respectively. TLC analysis was carried out on silica gel Roflumilast N-oxide plates GF254 (QingdaoHaiyang Chemical, Qingdao, China). Flash column chromatography was carried out on silica Roflumilast N-oxide gel 300C400 mesh. Anhydrous solvent and reagents were all analytical pure and dried through routine protocols. Methyl 2-(4-chlorophenyl)-2-(2-nitrophenylsulfonamido)acetate (3). Methyl 2-amino-2-(4-chlorophenyl)acetate hydrochloride (2, 2.15 g, 9.1 mmol) and = 4.3 Hz), 7.95C7.91 (m, 1H), 7.90C7.89 (m, 1H), 7.81C7.79 (m, 1H), 7.77C7.76 (m, 1H), 7.38C7.34 (m, 4H), 5.23 (d, 1H, = 4.3 Hz), 3.54 (s, 3H); ESI-MS (= 4.1 Hz), 7.43C7.42 (m, 1H), 7.33C7.32 (m, 2H), 7.29C7.27 (m, 2H), 7.20C7.17 (m, 1H), 6.69C6.53 (m, 1H), 6.53C6.50 (m, 1H), 5.90 (s, 2H), 4.96 (d, 1H, = 4.1 Hz), 3.48 (s, 3H); ESI-MS (= 8.4 Hz), 7.81C7.79 (m, 1H), 7.63C7.60 (m, 1H), 7.43C7.42 (m, 2H), 7.39C7.37 (m, 2H), 7.31C7.29 (m, 2H), 5.29 (d, 1H, = 8.0 Hz); ESI-MS (= 7.65 Hz), 7.35 (t, 1H, = 7.59 Rabbit Polyclonal to ARRC Hz), 7.15C7.09 (m, 3H), 6.89 (s, 2H), 5.96 (d, 1H, = 6.10 Hz), 5.84 (s, 1H), 4.77 (dd, 1H, = 2.38, 17.93 Hz), 4.66 (s, 1H), 4.50C4.47 (m, 1H), 4.19 (d, 1H, = 14.05 Hz), 3.29 (s, 1H). 13C-NMR (150 MHz, DMSO-= 7.86 Hz), 7.44 (d, 2H, = 7.98 Hz), 7.34 (s, 2H), 4.65C4.56 (m, 3H), 4.18 (d, 1H, = 18.93 Hz), 3.24 (d, 1H, = 18.26 Hz), 3.13 (t, 1H, = 2.44 Hz), 3.01 (s, 1H); 13C-NMR (75 MHz, DMSO-= 8.12 Hz), 7.37C7.33 (m, 4H), 7.24 (d, 1H, = 8.12 Hz), 4.94 (s, 1H), 4.17 (dd, 1H, = 2.3, 18.54 Hz), 3.40 (dd, 1H, = 2.3, 18.54 Hz); 13C-NMR (75 MHz, DMSO-= 8.47 Hz), 7.41C7.38 (m, 3H), 7.28 (d, 1H, = 8.07 Hz), 5.06 (s, 1H), 4.34 (d, 1H, = 18.58 Hz), 3.96 (d, 1H, = Roflumilast N-oxide 18.58 Hz); ESI-MS (= 14.4 Hz), 4.24 (d, 1H, = 14.4 Hz); ESI-MS (= 15.44 Hz), 4.16 (d, 1H, = 15.44 Hz); 13C-NMR (75 MHz, DMSO-= 9.6 Hz), 7.67C7.61 (m, 3H), 7.53C7.51 (m, 3H), 7.41 (d, 2H, = 8.2 Hz), 7.34 (d, 2H, = 8.2 Hz), 7.26 (s, 1H), 5.76 (s, 1H), 5.27 (s, 1H), 1.4 (s, 9H); ESI-MS (= 8.4 Hz), 7.53C7.51 (m, 3H), 7.47C7.43 (m, 4H), 7.34 (d, 1H, = 8.76 Hz), 7.30 (d, 1H, = 2.46 Hz), 4.87 (s, 1H); 13C-NMR (75 MHz, DMSO-= 8.4 Hz), 7.55C7.52 (m, 3H), 7.49C7.46 (m, 3H), 7.41 (d, 2H, = 8.4 Hz), 7.34 (d, 1H, = 2.4 Hz), 5.15 (s, 1H); 13C-NMR (75 MHz, DMSO-= 8.46 Hz), 7.52C7.49 (m, 5H), 7.47 (d, 1H, = 2.16 Hz), 7.45C7.43 (m, 2H), 5.61 (s, 1H); 13C-NMR (75 MHz, DMSO-= 8.46 Hz), 7.56 (dd, 1H, = 8.52 Hz), 7.33C7.29 (m, 7H), 7.01 (d, 1H, = 2.42 Hz), 5.29 (d, 1H, = 7.81 Hz), 5.19 (d, 1H, = 7.81 Hz), 4.32 (t, 1H, = 7.52 Hz); 13C-NMR (75 MHz, DMSO- em d /em 6): 153.29, 143.09, 141.91, 139.73, 138.26, 133.03, 132.49, 132.20, 130.53, 130.45, 129.85, 129.21, 128.58, 128.25, 127.34, 125.24, 59.74, 53.31; ESI-MS ( em m /em / em z /em ): 407.51 (M + H)+. 3.3. Computational Protocol Molecular docking was.