ABSTRACT
The P4 region of a series of oxamyl dipeptide caspase inhibitors was optimized by the combination of anti-apoptotic activity in the Jurkat/Fas (JFas) cellular assay and membrane permeability in the PAMPA assay. Two highly potent anti-apoptotic agents with moderate membrane permeability, 29 and 36, showed strong in vivo efficacy in a murine model of alpha-Fas-induced liver injury.
Subject(s)
Caspase Inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Liver Diseases/drug therapy , Animals , Apoptosis/drug effects , Cell Membrane Permeability/drug effects , Cysteine Proteinase Inhibitors/pharmacology , Humans , Jurkat Cells , Mice , Structure-Activity Relationship , fas ReceptorABSTRACT
Tertiary amides, ureas, and amines undergo direct intermolecular addition to aldehydes under the Et3B/air conditions, thereby providing a unique and simple means for the radical sp3 C-H transformation of nitrogen-containing molecules.
Subject(s)
Amides/chemical synthesis , Amines/chemical synthesis , Nitrogen/chemistry , Urease/chemical synthesis , Alkylation , Amides/chemistry , Amines/chemistry , Free Radicals/chemistry , Molecular Structure , Urease/chemistryABSTRACT
[reaction: see text] Epsilonthers and an acetal were found to undergo direct intermolecular addition to aldehydes under the Et(3)B/air conditions. This study presents a very unique and simple means for the radical alpha-C-H hydroxyalkylation of oxygen-containing compounds.
Subject(s)
Acetals/chemical synthesis , Ethers/chemical synthesis , Alkylation , Free Radicals/chemistry , Molecular ConformationABSTRACT
Alkoxyl radicals have a wide range of applications in organic synthesis due to their remarkable chemical properties in molecular transformation. The present study shows two types of alkoxyl radicals (primary vs tertiary) to selectively undergo dehydrogenation and beta-scission to give rise to key structural elements of (-)-CP-263,114 (1). By alkoxyl radical transformation followed by installation of the C19-C25 (CP numbering) side chain and the bridged bisacetal unit, the functionalized CP precursor 2 was obtained.
Subject(s)
Maleic Anhydrides/chemical synthesis , Magnetic Resonance Spectroscopy , Maleic Anhydrides/chemistryABSTRACT
The alpha-hydroxyalkylation of tetrahydrofuran with aldehydes via radical C-H abstraction was conducted using triethylborane in the presence of tert-butyl hydroperoxide. This study presents a rare instance of direct intermolecular radical addition of unactivated cyclic ether to aldehydes.
