期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 9, 页码 3739-3750出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501846y
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资金
- Korea Institute of Science and Technology (KIST)
- Creative/Challenging Research Program [2011-0028676]
- Global Research Network Research Program of the National Research Foundation of Korea (NRF) [NRF-220-2011-1-C00042]
- Korea Basic Science Institute [D33400]
- National Research Foundation of Korea [220-2011-1-C00042] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
We performed the first synthesis of the 17-carbon chain-tethered quinone moiety 22 (SAN5201) of irisferin A, a natural product exhibiting anticancer activity, and its derivatives. We found that 22 is a potent ROS inducer and cytotoxic agent. Compound 25 (SAN7401), the hydroquinone form of 22, induced a significant release of intracellular ROS and apoptosis (EC50 = 1.3-2.6 mu M) in cancer cell lines, including A549 and HCT-116. Compared with the activity of a well-known ROS inducer, piperlongumine, 22 and 25 showed stronger cytotoxicity and higher selectivity over noncancerous cells. Another hydroquinone tethering 12-carbon chain, 26 (SAN4601), generated reduced levels of ROS but showed more potent cytotoxicity (EC50 = 0.8-1.6 mu M) 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 25 and 26 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.
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