Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity

Calothrixin A (CAA)
is a dual Topo I and II inhibitor
but exhibits poor antiproliferative activities and water solubility.
Herein, a library of novel CAA analogues was synthesized.
Among them, compound F16 exhibited superior water solubility
(>5 mg/mL) as compared to CAA (<5 μg/mL).
The
mechanism of action studies confirmed that F16 acted
as a dual Topo I and II poison. Furthermore, F16 displayed
potent antiproliferative activities against high Topo I and II expression
cell lines A375 and HCT116, with IC50 values of 20 and
50 nM, respectively. In xenograft models, F16 reduced
the tumor growth at a dose of 10 or 20 mg/kg without apparent effect
on the mouse weight, while the clinically used Topo II inhibitor VP-16 dramatically reduced the mouse weight. Collectively,
our data demonstrated that F16 could be a promising lead
for the development of novel dual Topo I and II antitumor agents.