Please use this identifier to cite or link to this item: https://doi.org/10.1002/anie.201607303
Title: Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity
Authors: Zhang Chongjing 
Wang, Jigang
Zhang, Jianbin
LEE YEW MUN 
FENG GUANGXUE 
Lim Teck Kwang 
Shen, Han-Ming
Lin, Qingsong
LIU BIN 
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
anticancer activity
drug delivery
fluorescent probe
mitochondria targeting
triphenylphosphonium
TRADITIONAL CHINESE MEDICINE
PLASMODIUM-FALCIPARUM
ANTIMALARIAL-DRUGS
OXIDATIVE STRESS
IRON CHELATORS
HEME
CELLS
DESFERRIOXAMINE
MALARIA
STRATEGIES
Issue Date: 24-Oct-2016
Publisher: Wiley-VCH Verlag
Citation: Zhang Chongjing, Wang, Jigang, Zhang, Jianbin, LEE YEW MUN, FENG GUANGXUE, Lim Teck Kwang, Shen, Han-Ming, Lin, Qingsong, LIU BIN (2016-10-24). Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity. Angewandte Chemie - International Edition 55 (44) : 13770-13774. ScholarBank@NUS Repository. https://doi.org/10.1002/anie.201607303
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.
Source Title: Angewandte Chemie - International Edition
URI: https://scholarbank.nus.edu.sg/handle/10635/170707
ISSN: 1433-7851
1521-3773
DOI: 10.1002/anie.201607303
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