Discrete Cu(i) complexes for azide-alkyne annulations of small molecules inside mammalian cells.

Joan Miguel-Ávila,María Tomás-Gamasa,Andrea Olmos,José L. Mascareñas,Pedro J. Pérez

doi:10.1039/c7sc04643j

Abstract

The archetype reaction of "click" chemistry, namely, the copper-promoted azide-alkyne cycloaddition (CuAAC), has found an impressive number of applications in biological chemistry. However, methods for promoting intermolecular annulations of exogenous, small azides and alkynes in the complex interior of mammalian cells, are essentially unknown. Herein we demonstrate that isolated, well-defined copper(i)-tris(triazolyl) complexes featuring designed ligands can readily enter mammalian cells and promote intracellular CuAAC annulations of small, freely diffusible molecules. In addition to simplifying protocols and avoiding the addition of "non-innocent" reductants, the use of these premade copper complexes leads to more efficient processes than with the alternative, in situ made copper species prepared from Cu(ii) sources, tris(triazole) ligands and sodium ascorbate. Under the reaction conditions, the well-defined copper complexes exhibit very good cell penetration properties, and do not present significant toxicities.

Highlights

Organometallic catalysis has changed the eld of organic synthesis in the last half century, and has found important applications in other areas such as materials, energy or environmental sciences
While several groups have demonstrated the viability of achieving Suzuki or Sonogashira couplings on appropriately modi ed proteins in E. coli,[5] the only two examples described so far in mammalian cells involve the use of palladium nanoparticles, and xed cells.[6]
Our work was conceived on the hypothesis that designed, wellde ned Cu(I) complexes might cross cell membranes and keep their oxidation +1 state under the reductive atmosphere of the cell

Summary

Introduction

Organometallic catalysis has changed the eld of organic synthesis in the last half century, and has found important applications in other areas such as materials, energy or environmental sciences. We present data on the compared reactivity, redox stability, cell uptake and toxicity of in situ made copper species versus Cu(I) prede ned complexes.

Results

Conclusion