A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors

Barnes, N; Parker, AW; Mal Ullah, AA; Ragazzon, PA; Hadfield, JA

Abstract

A series of combretastatin derivatives were designed and synthesised by a two-step stereoselective synthesis by use of Wittig olefination followed by Suzuki cross-coupling. Interestingly, all new compounds (2a-2i) showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, 2a, 2b and 2e were the most active across three cancer cell lines. In addition, these compounds inhibited the polymerisation of tubulin in vitro more efficiently than CA-4. They caused cell cycle arrest in G2/M phase further confirming their ability to inhibit tubulin polymerisation.

Citation

Barnes, N., Parker, A., Mal Ullah, A., Ragazzon, P., & Hadfield, J. (2020). A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors. Bioorganic and Medicinal Chemistry, 28(19), 115684. https://doi.org/10.1016/j.bmc.2020.115684

• Journal Article Type: Article
• Acceptance Date: Jul 28, 2020
• Online Publication Date: Aug 5, 2020
• Publication Date: Oct 1, 2020
• Deposit Date: Aug 20, 2020
• Publicly Available Date: Aug 5, 2021
• Journal: Bioorganic and Medicinal Chemistry
• Print ISSN: 0968-0896
• Publisher: Elsevier
• Volume: 28
• Issue: 19
• Pages: 115684
• DOI: https://doi.org/10.1016/j.bmc.2020.115684
• Publisher URL: https://doi.org/10.1016/j.bmc.2020.115684
• Related Public URLs: http://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry/
• Additional Information: Funders : Kidscan;Engineering and Physical Sciences Research Council (EPSRC); Projects : Synthesis and Evaluation of Novel Antivascular Agents for Two-Photon Activation; Grant Number: KGR14; Grant Number: 1817912