Wednesday, October 21, 2020

Triple, Mutually Orthogonal Bioorthogonal Pairs through the Design of Electronically Activated Sulfamate-Containing Cycloalkynes

Yun Hu, Jessica M. Roberts, Henry R. Kilgore, Amirah S. Mat Lani, Ronald T. Raines, and Jennifer M. Schomaker

Journal of the American Chemical Society 2020

DOI: 10.1021/jacs.0c06725

Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds that are capable of fast and predictable reactions. The ability to easily modify S-, N-, and O-containing cyclooctynes (SNO-OCTs) enables electronic tuning of various SNO-OCTs to influence their cycloaddition rates with Type I–III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant reaction rate enhancements of a difluorinated SNO-OCT derivative, as compared to the parent scaffold, were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 5.13 M–1 s–1. Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications.

Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

Felix M. Paulussen, Gina K. Schouten, Carolin Moertl, Jolanda Verheul, Irma Hoekstra, Gregory M. Koningstein, George H. Hutchins, Aslihan Al...