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 designed molecule with capacity to alkylate DNA bulges has been prepared from readily available starting materials. The spirocyclic template utilized was designed on the basis of established architectures, and equipped with a mustard alkylating group. Preliminary studies confirm alkylation of specific bulged sequences, paving the way for second generation substrates with higher affinity.
Subject(s)
Alkylating Agents/chemical synthesis , DNA/genetics , DNA/metabolism , Nucleic Acid Conformation , Alkylating Agents/metabolism , Base Sequence/physiology , Binding Sites/physiologyABSTRACT
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
Bulged regions of nucleic acids are important structural motifs whose function has been linked to a number of key nuclear processes. Additionally, bulged intermediates have been implicated in the etiology of several genetic diseases and as targets for viral regulation. Despite these obvious ramifications, few molecules are capable of selective binding to bulged sequences. Prompted by the remarkable affinity of a natural product metabolite, we have designed and prepared a series of readily accessible synthetic agents with selective bulge binding activity. Furthermore, by screening a library of bulge-containing oligodeoxynucelotides, correlations between structure and affinity of the agents can be drawn. In addition to potential applications in molecular biology, the availability of these spirocyclic agents now opens the door for rational drug design.
