ABSTRACT
[structure: see text] The viability of proteins as targets of thermally and photoactivated enediynes has been confirmed at the molecular level. Model studies using a labeled substrate confirmed the efficacy of atom transfer from diyl radicals produced from enediynes to form captodatively stabilized carbon centered aminoacyl radicals, which then undergo either fragmentation or dimerization. To exploit this finding, a family of enediynes was developed using an intramolecular coupling strategy. Derivatives were prepared and used to target specific proteins, showing good correlation between affinity and photoinduced protein degrading activity. The findings have potential applications in the design of artificial chemical proteases and add to our understanding of the mechanism of action of the clinically important enediyne antitumor antibiotics.
Subject(s)
Alkenes/chemical synthesis , Alkynes/chemical synthesis , Muramidase/chemistry , Photosensitizing Agents/chemical synthesis , Receptors, Estrogen/chemistry , Serum Albumin, Bovine/chemistry , Alkenes/chemistry , Alkenes/radiation effects , Alkynes/chemistry , Alkynes/radiation effects , Animals , Binding Sites , Cattle , Humans , Molecular Structure , Muramidase/metabolism , Photochemistry , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Receptors, Estrogen/metabolism , Serum Albumin, Bovine/metabolism , Structure-Activity RelationshipABSTRACT
A series of photoactivated enediynes was prepared, and successfully employed for the selective degradation of target proteins.
Subject(s)
Oligosaccharides/chemical synthesis , Oligosaccharides/pharmacology , Proteins/drug effects , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , DNA Damage/drug effects , Electrophoresis, Polyacrylamide Gel , Histones/chemistry , Histones/drug effects , Indicators and Reagents , Photochemistry , Proteins/chemistry , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/drug effectsABSTRACT
A series of halogen-substituted cyclic enediynes were prepared with use of carbenoid coupling strategy. DFT analysis, initially used to identify synthesis candidates, was also employed to rationalize the propensity for cycloaromatization of the compounds. In all cases studied the halogen atom had a strongly retardative effect on the thermal Bergman cycloaromatization reaction. The isolation of the first C-9 monochloroenediyne is noteworthy, and may find application in prodrug design.