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Discovery of a Chiral Fluorinated Azetidin-2-one as a Tubulin Polymerisation Inhibitor with Potent Antitumour Efficacy by Tang, Hairong; Cheng, Jiayi; Liang, Yuru; Wang, Yang is a Chemistry article available to read on EtoBox.

What is Discovery of a Chiral Fluorinated Azetidin-2-one as a Tubulin Polymerisation Inhibitor with Potent Antitumour Efficacy about?

Inhibition of tubulin polymerisation with small molecules has been clinically validated as a promising therapy for multiple solid tumours. Herein, a series of chiral azetidin-2-ones were asymmetrically synthesised and biologically evaluated for antitumour activities. Among them, a chiral fluorinated azetidin-2-one, 18, was found to exhibit the most potent activities against five cancer cell lines, including a drug-resistant cell line, with IC values ranging from 1.0 to 3.6 nM. Further mechanistic studies revealed that the compound 18 worked by disrupting tubulin polymerisation, blocking the cell cycle in the G/M phase, inducing cellular apoptosis, and suppressing angiogenesis. Additionally, 18 exhibited higher human-microsomal metabolic stability and aqueous solubility compared to those of combretastatin A-4. Finally, 18 was also found to effectively inhibit tumour growth in a xenograft mice model with low toxicity and thus might be a promising lead for further clinical development.

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Author

Tang, Hairong; Cheng, Jiayi; Liang, Yuru; Wang, Yang

Publisher

Elsevier Science; Elsevier ; Elsevier BV (ISSN 0223-5234)

Published

2020

Language

EN

Field

Chemistry (Physical Sciences)