Synthesis and Antitumor Activities of Novel Mitochondria-Targeted Dihydroartemisinin Ether Derivatives

Abstract

Ten novel mitochondria-targeted dihydroartemisinin ether derivatives were designed, synthesized, and evaluated for antitumor activity against five cancer cell lines in vitro. Profoundly, compound D8-T (IC 50 = 56.9 nM) showed the most potent antiproliferative activity against the T24 cells with low cytotoxicity in normal human umbilical vein endothelial cells. Highperformance liquid chromatography analysis confirmed that D8-T targeted mitochondria 6.3-fold higher than DHA. ATP content assay demonstrated that D8-T decreased the ATP level of bladder cancer cells. The effect of D8-T on cell apoptosis was determined by flow cytometry and western blot of Bax and Bcl-2. Surprisingly, the results indicated that D8-T did not induce bladder cancer cell apoptosis. In contrast, the cell cycle analysis and western blot of CDK4, CDK6, cyclin D1, and p21 demonstrated that the cancer cell cycle was arrested at the G1 phase after D8-T treatment. Furthermore, the consistent results were received by RNA-seq assay. These promising findings implied that D8-T could serve as a great candidate against bladder cancer for further investigation.

Surface Molecularly Imprinted Cellulose‐Synthetic Hybrid Particles Prepared via ATRP for Enrichment of Flavonoids in Olive Leaf

“…The pyridyl group behaves as a proton acceptor (small nucleophilic molecule that can interact with exposed electrophilic residues), being also a good ligand for multiple metal ions, giving rise to complexation. Due to these particular properties, polymers based on 4VP are being considered for heavy metals ions adsorption and wastewater/industrial effluents treatment, [ 13–17 ] enzymes/protein adsorption, [ 18,19 ] and other applications involving electronics, biomedicine, or catalysis. [ 20 ]…”

A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death inducer

“… 28 The peroxy group that endows its antimalarial and anticancer activity can react with ferrous ions or heme to form highly reactive and toxic carbon-centered free radicals, leading to the alkylation of target proteins and oxidative stress in cells. 29 , 30 , 31 , 32 Currently, there are few studies on the role of DHA in inducing ICD, and the non-specific distribution of DHA in the cytoplasm results in a mild ICD effect. 33 We posited that the potential of ICD induction has not been fully realized due to the lack of mitochondria-targeting of DHA itself.…”