Design, Synthesis, and Biological Evaluation of Mitochondria-Targeted Flavone–Naphthalimide–Polyamine Conjugates with Antimetastatic Activity

Approximately
90% of cancer-associated deaths result from disseminated tumors, indicating
the ineffectiveness of current therapies and the imperative need of
antimetastatic drugs. A novel pharmacophore with flavonoid and naphthalimide
moieties was constructed by using a fragment-based drug design and
a series of eight flavone–naphthalimide–polyamine conjugates
were synthesized. In vitro evaluation revealed that
compound 6c with a homospermidine motif displayed better
cell selectivity between cancerous and normal liver cells than amonafide
did. The in vivo assays on two hepatocellular carcinoma
(HCC) models verified that 6c potently suppressed pulmonary
metastasis with improved organ indexes compared to amonafide. Various
experiments showed that 6c as a potential fluorescent
chemical probe could target the mitochondria. Preliminary investigation
into the mechanism of action of 6c indicated that it
might harness a polyamine transporter for cell entrance, localize
in the mitochondria, selectively cause reactive oxygen species (ROS)
overproduction in hepatoma cells instead of normal liver cells, and
finally lead to HCC cell apoptosis and migration inhibition via multiple
ROS-mediated signaling pathways.