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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Tang H,Liang Y,Cheng J,Ding K,Wang Ydoi
10.1016/j.ejmech.2021.113531keywords:
["1,4-Diarylazetidin-2-ones","Antitumor","Organoselenium","ROS","Tubulin"]subject
Has Abstractpub_date
2021-10-05 00:00:00pages
113531eissn
0223-5234issn
1768-3254pii
S0223-5234(21)00380-9journal_volume
221pub_type
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