Design, Synthesis, and Biological Characterization of Novel Mitochondria Targeted Dichloroacetate-Loaded Compounds with Antileukemic Activity

The
mitochondrial kinase inhibitor dichloroacetate (DCA) has recently
received attention in oncology due to its ability to target glycolysis.
However, DCA molecule exhibits poor bioavailability and cellular uptake
with limited ability to reach its target mitochondria. To overcome
these biases, we have synthesized novel DCA-loaded compounds. The
selection of the most promising therapeutic molecule was evaluated
by combining in vitro assays, to test the
antitumoral potential on leukemic cells, and a preliminary characterization
of the molecule stability in vivo, in mice. Among the newly synthesized
compounds, we have selected the multiple DCA-loaded compound 10, characterized by a tertiary amine scaffold, because it
exhibited enhanced (>30-fold) in vitro antitumor activity with
respect
to DCA and increased in vivo stability. On the basis of these results,
we believe that compound 10 should be considered for
further preclinical evaluations for the treatment of cancers and/or
other diseases characterized by altered metabolic origin.