Efficient Pictet-Spengler Bioconjugation with N-Substituted Pyrrolyl Alanine Derivatives.

Abstract

We discovered N-pyrrolyl alanine derivatives as efficient reagents for the fast and selective Pictet-Spengler reaction with aldehyde-containing biomolecules. Other aldehyde-labeling methods described so far have several drawbacks, like hydrolytic instability, slow reaction kinetics or not readily available labeling reagents. Pictet-Spengler cyclizations of pyrrolyl 2-ethylamine substituted at the pyrrole nitrogen are significantly faster than with analogues substituted at the α- and β- position. Functionalized N-pyrrolyl alanine derivatives can be synthesized in only 2-3 steps from commercially available materials. The small size of the reagent, the high reaction rate, and the easy synthesis make pyrrolyl alanine Pictet-Spengler (PAPS) an attractive choice for bioconjugation reactions. PAPS was shown as an efficient strategy for the site-selective biotinylation of an antibody as well as for the condensation of nucleic-acid derivatives, demonstrating the versatility of this reagent.