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  • Title: Bifunctional chiral selenium-containing 1,4-diarylazetidin-2-ones with potent antitumor activities by disrupting tubulin polymerization and inducing reactive oxygen species production.
    Author: Tang H, Liang Y, Cheng J, Ding K, Wang Y.
    Journal: Eur J Med Chem; 2021 Oct 05; 221():113531. PubMed ID: 34044345.
    Abstract:
    Organoselenium compounds have attracted growing interests as promising antitumor agents over recent years. Herein, four series of novel selenium-containing chiral 1,4-diarylazetidin-2-ones were asymmetrically synthesized and biologically evaluated for antitumor activities. Among them, compound 7 was found to be about 10-fold more potent than its prototype compound 1a, and compound 9a exhibited the most potent cytotoxicity against five human cancer cell lines, including a paclitaxel-resistant human ovarian cancer cell line A2780T, with IC50 values ranging from 1 to 3 nM. Mechanistic studies revealed that compound 9a worked by disrupting tubulin polymerization, inducing reactive oxygen species (ROS) production, decreasing mitochondrial membrane potential, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis and suppressing angiogenesis. Additionally, compound 9a exhibited appropriate human-microsomal metabolic stability and physicochemical properties. Importantly, compound 9a was found to inhibit tumor growth effectively in a xenograft mice model with low toxicity profile, which rendered 9a a highly promising candidate for further pre-clinical development.
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