A minimally-masked inactive prodrug of panobinostat that is bioorthogonally activated by gold chemistry

The recent incorporation of Au chemistry in the bioorthogonal toolbox has opened up new opportunities to deliver biologically independent reactions in living environments. Herein we report that the O-propargylation of the hydroxamate group of the potent HDAC inhibitor panobinostat leads to a vast reduction of its anticancer properties (>500-fold). We also show that this novel prodrug is converted back into panobinostat in the presence of Au catalysts in vitro and in cell culture.
We gratefully acknowledge financial support from EPSRC (EP/N021134/1 and EP/S010289/1). B.R.-R. thanks the EC (grant no. H2020-MSCA-IF-2014-658833). V.S. acknowledges the financial support of Ministerio de Ciencia, Innovación y Universidades, Programa Retos Investigación, Proyecto REF: RTI2018-099019-A-I00.