Antitumor and toxicity study of mitochondria-targeted triptolide derivatives using triphenylphosphine (TPP+) as a carrier. (15th November 2021)

• Record Type: Journal Article
• Authors: Song, Huina; Xing, Wenlan; Shi, Xiaojia; Zhang, Tao; Lou, Hongxiang; Fan, Peihong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 50(2021)
• Publication Date: 2021-11-15
• Subjects: Triptolide -- Mitochondria targeting -- DLCs -- Triphenylphosphine -- Zebrafish; Akt protein kinase B -- BCA bicinchoninic acid -- CH3CN acetonitrile -- DAPI 4′, 6-diamidino-2-phenylindole -- DCM dichloromethane -- DLCs delocalized lipophilic cations -- DMAP 4-dimethylaminopyridine -- DMEM Dulbecco's modified Eagle medium -- EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride -- FBS fetal bovine serum -- GSK-3β glycogen synthase kinase-3β -- hpf hours post fertilization -- HPLC high performance liquid chromatography -- HR-ESI-MS high resolution electrospray ionization mass spectrometry -- IC50 50% inhibition concentration -- J coupling constant -- JC-1 5, 5′, 6, 6′-tetrachloro-1, 1′, 3, 3′-tetraethylbenzimidazolocarbocyanine iodide -- LDH lactate dehydrogenase -- MeOH methanol -- Δψm mitochondrial membrane potential -- MRC mitochondrial respiratory chain -- mTOR mammalian target of rapamycin -- MTP (Mito-TP-2) -- MTT 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide -- NMR Nuclear magnetic resonance -- p70S6K p70 ribosomal protein S6 kinase -- PARP poly(ADP-ribose)polymerase -- PBS phosphate buffer saline -- PI Propidium -- ROS reactive oxygen species -- RP-HPLC reversed-phase high performance liquid chromatography -- SIRT3 sirtuin 3 -- TLC thinlayer chromatography -- TP triptolide -- TPP+ triphenylphosphine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116466
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Based on the higher mitochondrial membrane potential (Δψm ) of tumor cells than normal cells, a mitochondria-targeting strategy using delocalized lipophilic cations as carriers is a promising way to improve the antitumor effect of small molecules and to reduce toxicity. Triptolide (TP) has a strong antitumor effect but is limited in the clinic due to high systemic toxicity. Mitochondria-targeted TP derivatives were designed and synthesized using triphenylphosphine cations as carriers. The optimal derivative not only maintained the antitumor activity of TP but also showed a tumor cell selectivity trend. Moreover, the optimal derivative increased the release of lactate dehydrogenase and the production of ROS, decreased Δψm, and arrested HepG2 cells in G0/G1 phase. In a zebrafish HepG2 xenograft tumor model, the inhibitory effect of the optimal derivative was comparable to that of TP, while it had no obvious toxic effect on multiple indicators in zebrafish at the test concentrations. This work provided some evidence to support the mitochondria-targeting strategy.