Chemical Activation in Blood Serum and Human Cell Culture: Improved Ruthenium Complex for Catalytic Uncaging of Alloc-Protected Amines

Abstract

Chemical (as opposed to light-induced) activation of caged molecules is a rapidly advancing approach to trigger biological processes. We previously introduced the ruthenium-catalyzed release of allyloxycarbonyl (alloc)-protected amines in human cells. A restriction of this and all other methods is the limited lifetime of the catalyst, thus hampering meaningful applications. In this study, we addressed this problem with the development of a new generation of ruthenium complexes for the uncaging of alloc-protected amines with superior catalytic activity. Under biologically relevant conditions, we achieved a turnover number >300, a reaction rate of 580 m^-1 s^-1 , and we observed high activity in blood serum. Furthermore, alloc-protected doxorubicin, as an anticancer prodrug, could be activated in human cell culture and induced apoptosis with a single low dose (1 μm) of the new catalyst.

Keywords: bioorthogonal chemistry; cage compounds; catalysis; drug delivery; ruthenium; uncaging.