Novel cyanocombretastatins as potent tubulin polymerisation inhibitors

Jalily, Pouria; Hirst, N; Hadfield, JA; Rossington, SB

Abstract

A series of novel cyanocombretastatins bearing a 3,4,5-trimethoxyphenyl moiety combined with a variety of substituted phenyl rings, were synthesised and their antitumour activity was evaluated. The Z-cyanocombretastatins were synthesised in a one-step protocol in high purity and yield. Fluoro, bromo,
iodo, and derivatives with boronic acid and an ethyne function at meta position of the B ring were synthesised. In vitro MTT bioassays against human chronic myelogenous leukaemia (K562) and transfected breast adenocarcinoma (MDA NQO1) cell lines, revealed promising IC50 inhibitory values in nanomolar
range (<50 nM). Introduction of a nitrile function on the olefinic bond not only increased the cytotoxicity of the less active Z-isomers but rendered the analogues as moderate to potent inhibitors of tubulin polymerisation comparable to that of CA-4 (IC50 = 2.2 lM).

Citation

Jalily, P., Hirst, N., Hadfield, J., & Rossington, S. (2012). Novel cyanocombretastatins as potent tubulin polymerisation inhibitors. Bioorganic and Medicinal Chemistry Letters, 22(21), 6731-6734. https://doi.org/10.1016/j.bmcl.2012.08.089

• Journal Article Type: Article
• Acceptance Date: Aug 23, 2012
• Online Publication Date: Sep 6, 2012
• Publication Date: Sep 6, 2012
• Deposit Date: Oct 8, 2012
• Journal: Bioorganic and medicinal chemistry letters
• Print ISSN: 0960-894X
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 22
• Issue: 21
• Pages: 6731-6734
• DOI: https://doi.org/10.1016/j.bmcl.2012.08.089
• Publisher URL: http://dx.doi.org/10.1016/j.bmcl.2012.08.089
• Related Public URLs: http://www.sciencedirect.com/science/journal/0960894X/22/21