Hydrochalcogenation Reactions with Noncanonical Amino Acids as a Route to Increase Bioconjugate Valency

Bioconjugation represents an efficient and rapid mechanism to enhance the already extensive utility of proteins; however, it requires the development of additional chemistries to prevent undesired reactivity with nascent biological functionalities. Moreover, the ability to conjugate multiple partners to increase the conjugate valency further expands potential applications. Herein, we describe the development and optimization of a thio-yne bioconjugation using rongalite coupled with noncanonical amino acids (ncAAs) to afford multivalent conjugates. The site-specificity of the ncAA partner provides a functional handle to perform a biological Glaser-Hay reaction that installs the functionality for a secondary hydrochalcogenation. These trivalent conjugates serve as a proof-of-concept for the development of potent therapeutic and diagnostic agents that have vast applicability.