Identification of Novel ROS Inducers: Quinone Derivatives Tethered to Long Hydrocarbon Chains

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 (EC₅₀ = 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 (EC₅₀ = 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