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.

Methemoglobin as a redox-responsive nanocarrier to trigger the in situ anticancer ability of artemisinin

“…6,7 The in situ trigger mechanism provides the basis of its incredibly accurate toxicity to malarial parasites with extremely low side effects. 8 Recently, the potential generation of free radicals from ART has been considered as a promising way to treat cancers, [9][10][11] and iron is often co-delivered with ART to enhance the free radical generation. 12,13 However, it remains challenging to develop an effective in situ approach to trigger free radical generation reactions within tumors.…”

“…9,11,30 Herein, the potency of free ART and MHb-ART in inducing cancer cell apoptosis was studied. As seen in Figure 3, when the KB cells were treated with the MHb-ART complex, the total cell population of the early and late apoptosis state was significantly higher than for the free ART group.…”

Three pairs of enantiomers bearing mitochondria‐targeted TPP+ groups as potential anti‐cancer agents

“…Mitochondrial‐oriented delivery of anticancer drugs has been considered as a promising strategy because mitochondria play vital roles in cells . As the cellular powerhouse, mitochondria are responsible for generating most cellular energy in the form of ATP and regulating the intrinsic pathway of apoptosis, which serve as a cell suicide program to eliminate cells in the organism .…”

Directed Graphene‐Based Nanoplatforms for Hyperthermia: Overcoming Multiple Drug Resistance

“…[8c,d] In this work, nG was produced and functionalized by triazine,and consequently post-modified with hyperbranched polyglycerolamine (hPG NH 2 )according to previously reported methods. [6] Afterwards,t riphenylphosphonium (TPP; Scheme 1), amitochondrial targeting ligand, [9] was conjugated to the surface of the nanosystem. Polyglycerol-functionalized nG (GP) and their analogues with TPP ligands (GPT) were further functionalized by 2,3-dimethylmaleic anhydride (DA) to obtain graphene derivatives with pH-triggered surface charge conversion (GPD and GPTD,r espectively).…”

“…Intensive accumulations of GPTD in mitochondria, in comparison with GPD,s howed the efficiency of TPP as am itochondria targeting ligand ( Figure 2E). [9] Intracellular…”