Optimisation of tetrahydroisoquinoline-based chimeric microtubule disruptors

W. Dohle, M.P. Leese, F.L. Jourdan, C.J. Chapman, E. Hamel, E. Ferrandis, B.V.L. Potter

Research output: Contribution to journalArticlepeer-review

12 Citations (SciVal)


Tetrahydroisoquinoline (THIQ)-based "chimeric" microtubule disruptors were optimised through modification of the N-benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15: GI50 20 nM in DU-145). The broad anticancer activity of these novel structures was confirmed in the NCI 60-cell line assay, with 12 e,f displaying MGM values in the 40 nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15, for example, inhibited tubulin polymerisation with an IC50 of 1.8 μM, close to that of the clinical drug combretastatin A-4, and also proved effective at blocking colchicine binding. Additionally, compound 20 b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC=1.6 μM). Compound 12f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development.

Original languageEnglish
Pages (from-to)1783-1793
Number of pages11
Issue number8
Early online date12 May 2014
Publication statusPublished - Aug 2014


Dive into the research topics of 'Optimisation of tetrahydroisoquinoline-based chimeric microtubule disruptors'. Together they form a unique fingerprint.

Cite this