title: ent-Kaurane Diterpenoids from Chinese Liverworts and Their Antitumor Activities through Michael Addition As Detected in Situ by a Fluorescence Probe.
abstract: It is generally accepted that the origin of the cytotoxicity of ent-kaurane diterpenoids is due to the formation of reactive oxygen species (ROS) and that the α,β-unsaturated carbonyl is a pivotal moiety. Herein we demonstrate the isolation of 32 new and 12 known ent-kaurane diterpenoids from two Chinese liverworts. These compounds and three semisynthesized derivatives were screened against human cancer cell lines. The results revealed that their anticancer activities are caused by ROS formation through Michael modification of the protein thiols and depletion of glutathione unselectively. We also found that N-acetylcysteine reverses the cytotoxicity of these diterpenoids by forming Michael adducts, not through a well-recognized ROS scavenging pathway as previously reported. In situ intracellular thiol detection helped us visualize the intracellular distribution of the diterpenoids and determine the potency of their cytotoxicity. An alkaline analogue was found to be more selective because of the altered subcellular distribution.
authors: †Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Zhaomin
authors: Z
authors: Lin
authors: ‡Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Yanxia
authors: Y
authors: Guo
authors: †Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Yanhui
authors: Y
authors: Gao
authors: †Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Shuqi
authors: S
authors: Wang
authors: †Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Xiaoning
authors: X
authors: Wang
authors: †Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Zhiyu
authors: Z
authors: Xie
authors: ‡Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Huanmin
authors: H
authors: Niu
authors: †Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Wenqiang
authors: W
authors: Chang
authors: †Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Lei
authors: L
authors: Liu
authors: ‡Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Huiqing
authors: H
authors: Yuan
authors: †Department of Natural Products Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, People's Republic of China.
authors: Hongxiang
authors: H
authors: Lou
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry; D045786:Diterpenes, Kaurane / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005456:Fluorescent Dyes / Q000737:chemistry*; D035926:Hepatophyta / Q000737:chemistry*; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001386:Azides; D003374:Coumarins; D045786:Diterpenes, Kaurane; D005456:Fluorescent Dyes; D017382:Reactive Oxygen Species