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Optimisation of Tetrahydroisoquinoline‐Based Chimeric Microtubule Disruptors
Author(s) -
Dohle Wolfgang,
Leese Mathew P.,
Jourdan Fabrice L.,
Chapman Christopher J.,
Hamel Ernest,
Ferrandis Eric,
Potter Barry V. L.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402025
Subject(s) - tubulin , microtubule , colchicine , combretastatin , in vitro , tetrahydroisoquinoline , chemistry , in vivo , stereochemistry , biochemistry , biology , microbiology and biotechnology , genetics
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 : GI 50 20 n M 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 n M 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 IC 50 of 1.8 μ M , 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 50 =1.6 μ M ). Compound 12 f 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.