Recently, artemisinin and derivatives have been revealed to possess encouraging antitumor activity. Herein, we integrated the antitumor advantages of artesunate and platinum drugs to construct novel Pt IV −artesunate dual-action and tripleaction complexes. Most derivatives, especially 10f, displayed broadspectrum and potent in vitro antitumor activities against a number of cancer cell lines. Compound 10f displayed potent antimetastasis and anticlonogenic activities, efficiently induced autophagic cell death and apoptosis, and arrested the cell cycle at both S and G2/M phases. More importantly, it displayed remarkable in vivo antitumor efficacy in the A549 xenograft model (TGI = 53.4%; 6 μmol/kg) with low toxicity. In addition to the antitumor application, 10f showed potent in vivo antimalarial activity in malarial-infected mice model and obviously alleviated malarial-related multiorgan injury. This conjugation greatly improved safety, especially reducing the platinum drugs' nephrotoxicity. Taken together, this study highlighted the therapeutic potential of Pt IV −artesunate complexes as antitumor and antimalarial agents.
The colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum
in vitro
antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues
C1∼J2
bearing diverse substituents and scaffolds. Among them, analogue
G13
bearing a hydroxymethyl group displayed good tubulin polymerisation inhibitory activity (IC
50
= 13.5 μM) and potent antiproliferative activity (IC
50
values: 0.65 μM∼0.90 μM).
G13
potently inhibited the migration and invasion of MDA-MB-231 cells, and displayed potent antiangiogenic activity. It efficiently increased intracellular ROS level and decreased MMP in cancer cells, and obviously induced the fragmentation and disassembly of the microtubules network. More importantly,
G13
exhibited good
in vivo
antitumour efficacy in MDA-MB-231 xenograft model (TGI = 38.2%; i.p., 30 mg/kg).
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