title: Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity.
abstract: Understanding the mechanism of action (MOA) of bioactive natural products will guide endeavor to improve their cellular activities. Artemisinin and its derivatives inhibit cancer cell proliferation, yet with much lower efficiencies than their roles in killing malaria parasites. To improve their efficacies on cancer cells, we studied the MOA of artemisinin using chemical proteomics and found that free heme could directly activate artemisinin. We then designed and synthesized a derivative, ART-TPP, which is capable of targeting the drug to mitochondria where free heme is synthesized. Remarkably, ART-TPP exerted more potent inhibition than its parent compound to cancer cells. A clickable probe ART-TPP-Alk was also employed to confirm that the attachment of the TPP group could label more mitochondrial proteins than that for the ART derivative without TPP (AP1). This work shows the importance of MOA study, which enables us to optimize the design of natural drug analogues to improve their biological activities.
authors.affiliation: Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore.
authors.forename: Chong-Jing
authors.identifier: 0000-0003-4529-4906
authors.initials: CJ
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, Nanjing, 210023, China. wangjg@nju.edu.cn.|Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore. wangjg@nju.edu.cn.
authors.forename: Jigang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore, 117597, Singapore.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Yew Mun
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore.
authors.forename: Guangxue
authors.initials: G
authors.lastname: Feng
authors.affiliation: Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Teck Kwang
authors.initials: TK
authors.lastname: Lim
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore, 117597, Singapore.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.affiliation: Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore. dbslinqs@nus.edu.sg.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore. cheliub@nus.edu.sg.|Institute of Materials Research and Engineering, 2 Fusionopolis Way, Singapore, 138634, Singapore. cheliub@nus.edu.sg.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; C031327:artemisinin
keywords: anticancer activity; drug delivery; fluorescent probe; mitochondria targeting; triphenylphosphonium