A novel selective mitochondrial-targeted curcumin analog with remarkable cytotoxicity in glioma cells

• Published in: European journal of medicinal chemistry Vol. 221; pp. 113528 - 113539
• Main Authors: Shi, Lei, Gao, Li-li, Cai, Shi-zhong, Xiong, Qian-wei, Ma, Zhou-rui
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.10.2021; Elsevier
• Subjects: Chemistry, Medicinal; Curcumin; Demethoxycurcumin; Glioma; Life Sciences & Biomedicine; Mitochondrial-targeting; Pharmacology & Pharmacy; Science & Technology; Thioredoxin reductase; Demethoxycurcumin; Curcumin; Glioma; Mitochondrial-targeting; Thioredoxin reductase; SYSTEM; APOPTOSIS; INHIBITION; DERIVATIVES; EXPRESSION
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113528

Naturally occurring polyphenol curcumin (4) or demethoxycurcumin (5) and their synthetic derivatives display promising anticancer activities. However, their further development is limited by low bioavailability and poor selectivity. Thus, a mitochondria-targeted compound 14 (DMC-TPP) was prepared in the present study by conjugating a triphenylphosphine moiety to the phenolic hydroxyl group of demethoxycurcumin to enhance its bioavailability and treatment efficacy. The in vitro biological experiments of DMC-TPP showed that it not only displayed higher cytotoxicity as compared with its parent compound 5, but also exhibited superior mitochondria accumulation ability. Glioma cells were more sensitive to DMC-TPP, which inhibited the proliferation of U251 cells with an IC50 of 0.42 μM. The mechanism studies showed that DMC-TPP triggers mitochondria-dependent apoptosis, caused by caspase activation, production of reactive oxygen species (ROS) and decrease of mitochondrial membrane potential (MMP). In addition, DMC-TPP efficiently inhibited cellular thioredoxin reductase, which contributed to its cytotoxicity. Significantly, DMC-TPP delayed tumor progression in a mouse xenograft model of human glioma cancer. Taken together, the potent in vitro and in vivo antitumor activity of DMC-TPP warrant further comprehensive evaluation as a novel anti-glioma agent. [Display omitted] •A novel selective mitochondria-targeted curcumin analog DMC-TPP was prepared.•DMC-TPP exhibited potent cytotoxic effects in glioma cells.•DMC-TPP efficiently inhibited cellular thioredoxin reductase.•DMC-TPP delayed tumor progression in a mouse xenograft model of human glioma cancer.