ABSTRACT
A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Binding Sites , Computer-Aided Design , Enzyme Inhibitors/blood , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity Relationship , Triazoles/blood , Triazoles/chemistryABSTRACT
[reaction: see text]. Retrocycloadditions of 4H-4-alkyl-5-(trialkylsilyloxy)-1,3-dioxins proceed smoothly in refluxing toluene to afford (Z)-2-(trialkylsilyloxy)-2-alkenals with complete stereoselectivity. These enals undergo Sasaki-type [4 + 3] cyclizations with dienes in the presence of Lewis acids, in many instances with excellent regio- and/or stereoselectivity.
Subject(s)
Alkenes/chemistry , Dioxins/chemistry , Siloxanes/chemistry , Catalysis , Cyclization , StereoisomerismABSTRACT
[reaction: see text] A convergent total synthesis of illudin C is described. The tricyclic ring system of the natural product was quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide-olefin cycloaddition.
