In a preliminary investigation, we have found that (i) m-fluorophenol and derivatives of 4-fluorotryptophan undergo a novel photonucleophilic displacement reaction of the fluoro group, (ii) derivatives of 4-chlorotryptophan and 4-chloroindoles undergo an equally interesting but entirely different photochemical dissociation to generate indolyl radicals, and (iii) m-chlorophenol undergoes either process depending on the polarity of the solvent. It has been reported previously that o-chlorophenol undergoes a Photo-Wolff Rearrangement, i.e., a ring-contraction to form a ketene intermediate. We propose to carry out a systematic investigation on the photochemistry of halophenols, 4-haloindoles, halotyrosines and 4-halotrytophans in order to achieve a mechanistic understanding with regard to the dependence of the reactive intermediate in these reactions on the structure of the aryl halide and experimental conditions. Since halotyrosines and 4-halotryptophans may be incorporated into proteins and peptides by conventional methods of solid-phase peptide synthesis and/or by methods of molecular biology, while existing photoaffinity labels cannot, and all proteins contain aromatic amino acids, photochemistry of halotyrosines and halotryptophans may be developed into new powerful methods of photoaffinity labelling in protein chemistry. Therefore, we also propose to explore the use of these compounds as photoaffinity labels in collaboration with scientists both at the University of Chicago and elsewhere, systems proposed include chymotrypsin, arylsulfatases, Trp repressor, retinoid binding proteins and insulin:receptor interaction. Additional systems may be developed as our work progresses. Furthermore, since covalent binding between proteins and their substrates or receptors may cause a profound modification of their biological functions, our study may lead to the design of new drugs and other biologically active agents.
| Locke, B C; MacInnis, J M; Qian, S et al. (1992) Fluorescence studies of rat cellular retinol binding protein II produced in Escherichia coli: an analysis of four tryptophan substitution mutants. Biochemistry 31:2376-83 |
