Identification of Novel ROS Inducers: Quinone Derivatives
Tethered to Long Hydrocarbon Chains
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Abstract
We performed the first synthesis
of the 17-carbon chain-tethered
quinone moiety <b>22</b> (SAN5201) of irisferin A, a natural
product exhibiting anticancer activity, and its derivatives. We found
that <b>22</b> is a potent ROS inducer and cytotoxic agent.
Compound <b>25</b> (SAN7401), the hydroquinone form of <b>22</b>, induced a significant release of intracellular ROS and
apoptosis (EC<sub>50</sub> = 1.3–2.6 μM) in cancer cell
lines, including A549 and HCT-116. Compared with the activity of a
well-known ROS inducer, piperlongumine, <b>22</b> and <b>25</b> showed stronger cytotoxicity and higher selectivity over
noncancerous cells. Another hydroquinone tethering 12-carbon chain, <b>26</b> (SAN4601), generated reduced levels of ROS but showed more
potent cytotoxicity (EC<sub>50</sub> = 0.8–1.6 μM) in
cancer cells, although it lacked selectivity over noncancerous cells,
implying that the naturally occurring 17-carbon chain is also crucial
for ROS production and a selective anticancer effect. Both <b>25</b> and <b>26</b> displayed strong, equipotent activities against
vemurafenib-resistant SK-Mel2 melanoma cells and p53-deficient H1299
lung cancer cells as well, demonstrating their broad therapeutic potential
as anticancer agents