Abstract:Dimethyl tetrahydropyranyloxymalonate reacts with hydrazobenzene to give 3 : S-dioxo-1 : 2-diphenyl-4-tetrahydropyranyloxypyrazolidine. Removal of the tetrahydropyranyl group afforded 4-hydroxy-3 : 6-dioxo-1 : 2diphenylpyrazolidine. A series of 4-alkoxy-3 : S-dioxo-1 : 2-diphenylpyrazolidines has been prepared by interaction of alkoxymalonic esters with hydrazobenzene. 4-Alkoxy-3-hydroxy-1 : 2-diphenylpyrazolin-6-ones were isolated directly from condensations utilising diethyl methoxy-and ethoxymalonic esters;… Show more
“…Deprotection of 13 gave compound 14 . 1 Synthetic Routes of 5-Substituted Pyrazole-3-yl Urea Derivatives a a Reagents: (a) (1) BuLi, CH 3 CN, tetrahydrofuran; (2) NH 2 NH 2 , EtOH, 40% (for 4 ), 81% (for 11 ); (b) NaH, (Boc) 2 O, tetrahydrofuran, 53% (for 5 ), 61% (for 12 ); (c) (1) 4-(dimethylamino)pyridine, p -nitrophenyl chloroformate, CHCl 3 ; (2) amine; (3) 4 N HCl, MeOH, 19%; (d) Pd(OH) 2 /C, H 2 , 2 N HCl, MeOH−tetrahydrofuran, 93%; (e) MnO 2 , CHCl 3 −dimethylformamide, 59%; (f) (1) alkylamine, MS3Å, chloroform−MeOH; (2) NaBH 4 , 20−50%; (g) (1) NaH, 4-nitrophenyl chloroformate, tetrahydrofuran; (2) amine, 4-(dimethylamino)pyridine, 42%; (3) 6 N HCl, MeOH, 21%; (h) Pd/C, H 2 , 4 N HCl, MeOH, 51%. …”
Section: Resultsmentioning
confidence: 99%
“…To a stirred solution of acetonitrile (10.2 mL, 195 mmol) in tetrahydrofuran (500 mL) was added butyllithium (130 mL, 1.5 M solution of hexane, 196 mmol) at -78 °C. After the solution was stirred for 30 min at the same temperature, ethyl benzyloxyacetate (3) 25 (34.0 g, 178 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then poured into water.…”
“…To a stirred solution of 12 (2.26 g, 6.6 mmol) in tetrahydrofuran (30 mL) was added NaH (60 wt % in mineral oil, 344 mg, 8.6 mmol). After the solution was stirred for 30 min at room temperature, 4-nitrophenyl chloroformate (1.73 g, 8.6 mmol) was added and stirred for an additional 30 min; subsequently, 4-(dimethylamino)pyridine (960 mg, 7.9 mmol) and 9-amino-1,2,3,9btetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one 25 (1.62 g, 8.6 mmol) was added. The reaction mixture was stirred for 12 h at 60 °C, poured into 1 N NaOH, and extracted with CHCl3.…”
Identification of a selective inhibitor for a particular protein kinase without inhibition of other kinases is critical for use as a biological tool or drug. However, this is very difficult because there are hundreds of homologous kinases and their kinase domains including the ATP binding pocket have a common folding pattern. To address this issue, we applied the following structure-based approach for designing selective Cdk4 inhibitors: (1) identification of specifically altered amino acid residues around the ATP binding pocket in Cdk4 by comparison of 390 representative kinases, (2) prediction of appropriate positions to introduce substituents in lead compounds based on the locations of the altered amino acid residues and the binding modes of lead compounds, and (3) library design to interact with the altered amino acid residues supported by de novo design programs. Accordingly, Asp99, Thr102, and Gln98 of Cdk4, which are located in the p16 binding region, were selected as first target residues for specific interactions with Cdk4. Subsequently, the 5-position of the pyrazole ring in the pyrazol-3-ylurea class of lead compound (2a) was predicted to be a suitable position to introduce substituents. We then designed a chemical library of pyrazol-3-ylurea substituted with alkylaminomethyl groups based on the output structures of de novo design programs. Thus we identified a highly selective and potent Cdk4 inhibitor, 15b, substituted with a 5-chloroindan-2-ylaminomethyl group. Compound 15b showed higher selectivity on Cdk4 over those on not only Cdk1/2 (780-fold/190-fold) but also many other kinases (>430-fold) that have been tested thus far. The structural basis for Cdk4 selective inhibition by 15b was analyzed by combining molecular modeling and the X-ray analysis of the Cdk4 mimic Cdk2-inhibitor complex. The results suggest that the hydrogen bond with the carboxyl group of Asp99 and hydrophobic van der Waals contact with the side chains of Thr102 and Gln98 are important. Compound 15b was found to cause cell cycle arrest of the Rb(+) cancer cell line in the G(1) phase, indicating that it is a good biological tool.
“…Deprotection of 13 gave compound 14 . 1 Synthetic Routes of 5-Substituted Pyrazole-3-yl Urea Derivatives a a Reagents: (a) (1) BuLi, CH 3 CN, tetrahydrofuran; (2) NH 2 NH 2 , EtOH, 40% (for 4 ), 81% (for 11 ); (b) NaH, (Boc) 2 O, tetrahydrofuran, 53% (for 5 ), 61% (for 12 ); (c) (1) 4-(dimethylamino)pyridine, p -nitrophenyl chloroformate, CHCl 3 ; (2) amine; (3) 4 N HCl, MeOH, 19%; (d) Pd(OH) 2 /C, H 2 , 2 N HCl, MeOH−tetrahydrofuran, 93%; (e) MnO 2 , CHCl 3 −dimethylformamide, 59%; (f) (1) alkylamine, MS3Å, chloroform−MeOH; (2) NaBH 4 , 20−50%; (g) (1) NaH, 4-nitrophenyl chloroformate, tetrahydrofuran; (2) amine, 4-(dimethylamino)pyridine, 42%; (3) 6 N HCl, MeOH, 21%; (h) Pd/C, H 2 , 4 N HCl, MeOH, 51%. …”
Section: Resultsmentioning
confidence: 99%
“…To a stirred solution of acetonitrile (10.2 mL, 195 mmol) in tetrahydrofuran (500 mL) was added butyllithium (130 mL, 1.5 M solution of hexane, 196 mmol) at -78 °C. After the solution was stirred for 30 min at the same temperature, ethyl benzyloxyacetate (3) 25 (34.0 g, 178 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then poured into water.…”
“…To a stirred solution of 12 (2.26 g, 6.6 mmol) in tetrahydrofuran (30 mL) was added NaH (60 wt % in mineral oil, 344 mg, 8.6 mmol). After the solution was stirred for 30 min at room temperature, 4-nitrophenyl chloroformate (1.73 g, 8.6 mmol) was added and stirred for an additional 30 min; subsequently, 4-(dimethylamino)pyridine (960 mg, 7.9 mmol) and 9-amino-1,2,3,9btetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one 25 (1.62 g, 8.6 mmol) was added. The reaction mixture was stirred for 12 h at 60 °C, poured into 1 N NaOH, and extracted with CHCl3.…”
Identification of a selective inhibitor for a particular protein kinase without inhibition of other kinases is critical for use as a biological tool or drug. However, this is very difficult because there are hundreds of homologous kinases and their kinase domains including the ATP binding pocket have a common folding pattern. To address this issue, we applied the following structure-based approach for designing selective Cdk4 inhibitors: (1) identification of specifically altered amino acid residues around the ATP binding pocket in Cdk4 by comparison of 390 representative kinases, (2) prediction of appropriate positions to introduce substituents in lead compounds based on the locations of the altered amino acid residues and the binding modes of lead compounds, and (3) library design to interact with the altered amino acid residues supported by de novo design programs. Accordingly, Asp99, Thr102, and Gln98 of Cdk4, which are located in the p16 binding region, were selected as first target residues for specific interactions with Cdk4. Subsequently, the 5-position of the pyrazole ring in the pyrazol-3-ylurea class of lead compound (2a) was predicted to be a suitable position to introduce substituents. We then designed a chemical library of pyrazol-3-ylurea substituted with alkylaminomethyl groups based on the output structures of de novo design programs. Thus we identified a highly selective and potent Cdk4 inhibitor, 15b, substituted with a 5-chloroindan-2-ylaminomethyl group. Compound 15b showed higher selectivity on Cdk4 over those on not only Cdk1/2 (780-fold/190-fold) but also many other kinases (>430-fold) that have been tested thus far. The structural basis for Cdk4 selective inhibition by 15b was analyzed by combining molecular modeling and the X-ray analysis of the Cdk4 mimic Cdk2-inhibitor complex. The results suggest that the hydrogen bond with the carboxyl group of Asp99 and hydrophobic van der Waals contact with the side chains of Thr102 and Gln98 are important. Compound 15b was found to cause cell cycle arrest of the Rb(+) cancer cell line in the G(1) phase, indicating that it is a good biological tool.
“…(2 R,S )-BnONH-Mal(OBn)-OH (7). EtO-Mal(OBn)-OEt was converted to the title compound as described for 2 : yield 58% over the two steps; colorless powder; TLC (CH 3 CN/H 2 O, 4:1) R f 0.25; 1 H NMR (DMSO- d 6 ) δ 13.1 (s (br), 1H, COOH), 11.50 (s, 1H, NH), 7.3−7.4 (m, 10H, 2 C 6 H 5 ), 4.83 (s, 2H, CH 2 (BnONH)), 4.53 (2 d, 2H, CH 2 (OBn)), 4.34 (s, 1H, H-C2 (Mal)).…”
For most of the known synthetic inhibitors of matrix metalloproteinases (MMPs), a substrate-like binding mode was postulated on the basis of X-ray crystallographic structures of MMP/inhibitor complexes. Conversely, the malonic acid-based inhibitor (2R,S)-HONH-CO-CH(i-Bu)-CO-Ala-Gly-NH2 was found to bind in a surprisingly different manner. Using this compound as a new lead structure, the interaction sites with human neutrophil collagenase (MMP8) were optimized with a series of iteratively designed analogues and with the help of X-ray structural analysis of selected inhibitors to finally produce low molecular weight nonpeptidic compounds of 500-1000-fold improved inhibitory potency.
Novel cyclol derivatives (Table 1, 15, 16) similar in structure to the peptide portion of ergocornine were synthesized. Detailed experimental procedures are given for the preparation of the cis‐13a and the unknown trans‐14a cyclol esters.
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