Discovery of novel conformationally restricted diazocan peptidomimetics as inhibitors of interleukin-1β synthesis

Small Molecule Active Site Directed Tools for Studying Human Caspases

“…Monocyclic 8-membered lactams have been designed to specifically target caspase-1. 283 This new scaffold allows introduction of numerous substituents at nitrogen-5 of the lactam moiety to efficiently explore new binding interactions with the caspase-1 S3 pocket. This group of inhibitors can selectively target caspase-1 over caspase-3 and -8, but the most potent inhibitor displays lower affinity for caspase-1 than Pralnacasan 77 (IC 50 of 15 nM and 2 nM respectively).…”

Solvent‐Enhanced Diastereo‐ and Regioselectivity in the PdII‐Catalyzed Synthesis of Six‐ and Eight‐Membered Heterocycles via cis‐Aminopalladation

“…This uncommon structure is also valuable as concerns natural product [7] and peptidomimetic [8] synthesis. In an investigation of the effect of the reaction medium on the regioselectivity, the 1 H NMR spectrum of the crude product indicated that diazocinone 14 was formed as the major product in refluxing toluene in an approximate Scheme 1.…”

“…The combined organic phase was dried over anhydrous Na 2 SO 4 and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (n-hexane/ethyl acetate 4:1), which provided pure compounds 9-15, 17, 18, 23 and 24. (2R * ,4aR -vinyl-2,3,4a,5,6,7,8,8a-octahydro-1H-quinazolin-4-one (9) 4, 24.7, 24.9, 30.9, 39.9, 45.3, 53.0, 69.8, 117.5, 119.9, 126.8, 130.1, 132.4, 136.4, 136.9, 144.0, 166.7 ppm;IR (KBr): ñ = 3079, 2960, 2942, 2865, 1935, 1655, 1445, 1343, 1246, 1168, 1090 14,H 7.00,N 7.48;found: C 64.02,H 7.12,2,6a,7,8,9,10, 4, 23.9, 24.9, 28.6, 28.7, 41.9, 44.4, 49.4, 58.2, 117.1, 118.1, 126.9, 127.0, 130.3, 134.1, 138.8, 143.4, 171.8 ppm;IR (KBr): ñ = 3085, 3067, 2924, 2864, 1935, 1834, 1654, 1445, 1396, 1336, 1221, 1154, 1090 14,H 7.00,N 7.48;found: C 64.01,H 6.82,3,6a,7,8,9,10, -4,6-dione (24): Pr...…”

“…General procedure for the cyclization of carboxamides [5][6][7][8]16 and 21: A 100 mL three-necked round-bottomed flask was charged with carboxamide 5-8 or 16 (1.3 mmol), NaOAc (106 mg, 1.3 mmol), nBu 4 NCl (362 mg, 1.3 mmol),…”

“…[2] However, the exact mechanism underlying this transformation has not been fully revealed to date, [1k] though it would be a powerful tool for the development of enantioselective Pd II -catalyzed cyclizations. [3] In view of the report by Beccalli et al on the oxidative Pd II -mediated cyclization of N-allylanthranilamides, involving marked solvent and base effects, [4] together with our particular interest in the synthesis and transformation of alicyclic b-amino acid derivatives, [5] the aim of the present work was to investigate the cyclization properties of cis-and trans-N,N-diallyl-(5, 7) and N-allyl-N-methyl-2-tosylaminocyclohexanecarboxamides (6,8) in Pd II -catalyzed intramolecular oxidative aminations. We have paid special attention to the possible stereochemical outcome of the transformations and to the effects of the marked difference between the calculated pK a values of the tosyl-protected cyclohexylamine-type nitrogen and the analogous aniline-type nitrogen [4] (9.9 vs 7.2).…”