| Summary: | The multifunctional linker molecules are crucial for the bio-orthogonal reaction for proteomic target profiling. Herein, we wish to present a novel type of biotin-based tetra-functional bio-orthogonal linkers <b>3a–3h</b> named BPPA which, possessing a unique photolabile phenacyl ester motif, were readily prepared in 85–90% yields by a simple and green one-step protocol from commercially available and inexpensive reagents of biotin acids and 4’-ethynyl/azido 2-bromoacetophenones. The typical click reaction of BPPA linkers <b>3a</b> and <b>3e</b> via copper-catalyzed azide–alkyne cycloaddition (CuAAC) took place easily, resulting in the corresponding BPPA-triazole adducts <b>4a</b> and <b>4b</b> in nearly quantitative yields. A further cleavability evaluation of <b>4a</b> and <b>4b</b> demonstrated that the expected C-O bond detachment could be accomplished efficiently and rapidly by UV irradiation or by ammonia hydrolysis, respectively, resulting in the residual (hydroxyl)acetylphenyl triazole fragment supposed to be attached to proteins during biological manipulations. The BPPA linkers, with dual clickable options of either the terminal azide or alkyne clickable group, exhibit high potentials for various CuAAC-oriented bio-orthogonal reactions.
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