title: 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 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 μM) 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 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 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.
authors.affiliation: †KU-KIST Graduate School of Converging Science and Technology, 145 Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea.
authors.forename: Yeonsun
authors.initials: Y
authors.lastname: Hong
authors.affiliation: ‡Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul, 136-791, Republic of Korea.
authors.forename: Sandip
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: ‡Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul, 136-791, Republic of Korea.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.affiliation: †KU-KIST Graduate School of Converging Science and Technology, 145 Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea.|‡Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul, 136-791, Republic of Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D000475:Alkenes; D000970:Antineoplastic Agents; D016227:Benzoquinones; D006873:Hydroquinones; D007211:Indoles; D011809:Quinones; D017382:Reactive Oxygen Species; C000599949:SAN5201; C000599950:SAN7401; D013449:Sulfonamides; D000077484:Vemurafenib