Abstract
The challenge of site-selectivity must be overcome in many chemical research contexts, including selective functionalization in complex natural products and labeling of one biomolecule in a living system. Synthetic catalysts incorporating molecular recognition domains can mimic naturally-occurring enzymes to direct a chemical reaction to a particular instance of a functional group. We propose that DNA-conjugated small molecule catalysts (DCats), prepared by tethering a small molecule catalyst to a DNA aptamer, are a promising class of reagents for site-selective transformations. Specifically, a DNA-imidazole conjugate able to increase the rate of ester hydrolysis in a target ester by >100-fold compared with equimolar untethered imidazole was developed. Other esters are unaffected. Furthermore, DCat-catalyzed hydrolysis follows enzyme-like kinetics and a stimuli-responsive variant of the DCat enables programmable "turn on" of the desired reaction.
Highlights
The challenge of site-selectivity must be overcome in many chemical research contexts, including selective functionalization in complex natural products and labeling of one biomolecule in a living system
The results presented far suggest that target recognition and binding is essential for the enhanced rate of DNA-conjugated small molecule catalysts (DCats)-catalyzed hydrolysis of 1, and other esters not recognized by the DCat's DNA aptamer domain should not be affected
Synthetic catalysts that incorporate molecular recognition domains offer a strategy for achieving the site-selective transformation of one instance of a functional group
Summary
The challenge of site-selectivity must be overcome in many chemical research contexts, including selective functionalization in complex natural products and labeling of one biomolecule in a living system. In analogy to biological enzymes, synthetic and semisynthetic catalysts incorporating molecular recognition elements to promote substrate binding and accelerate a desired reaction have been investigated.[7] Site-selectivity within vancomycin was demonstrated using peptide catalysts incorporating a vancomycin-binding domain7a and site-selectivity for protein labeling on live cell surfaces has been achieved using a reagent modularly assembled from a reactive small molecule catalyst and an antibody binding domain.[8] Like proteins, nucleic acids may fold into three-dimensional structures that confer a speci c function, with the additional advantages that they may be evolved to bind nearly any target de novo, synthesized and cheaply, and denatured reversibly.[9] Given the promise and challenge of site-selective catalysis with peptide or protein recognition domains,[7] we have initiated a research program to develop a class of catalysts that instead rely upon nucleic acid binding domains. Analysis of hydrolysis kinetics reveals that DCat[1] is 100 times more effective per mole than free small molecule catalyst, and comparison of target and nontarget esters illustrates that the DCat is highly site-selective
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