Optimisation of tetrahydroisoquinoline-based chimeric microtubule disruptors

Abstract

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 (IC50=.6 μM). 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.

Keywords: chimeras; colchicine binding; microtubule disruptors; tetrahydroisoquinolines; tubulin assembly.

Figure 1

Generation of small-molecule chimeric microtubule disruptors (Y=H-bond acceptor).

Scheme 1

Synthesis of 7-methoxy-THIQs. Reagents and conditions: a) ArCH₂Cl, Et₃N, EtOH, 130 °C, MW; b) ArCH₂Br, DIPEA, DMF, 80 °C; c) ArCO₂H, EDCI, CH₂Cl₂/THF, 25 °C; d) LiAlH₄, THF, reflux; e) H₂, Pd/C, THF/MeOH, 25 °C; f) TBAF, THF, 25 °C; g) H₂NSO₂Cl, DMA, 25 °C.

Scheme 2

Synthesis of 7-ethyl-THIQs. Reagents and conditions: a) 3-Bromo-4,5-dimethoxybenzyl bromide, DIPEA, DMF, 80 °C, 20 h, 40%; b) H₂NSO₂Cl, DMA, 25 °C, 20 h, 47%.

Scheme 3

Synthesis of C6-modified THIQs. Reagents and conditions: a) 3,4,5-Trimethoxybenzyl chloride, Et₃N, EtOH, 130 °C, MW, 1 h, 62%; b) Ac₂O, Et₃N, CHCl₃, 25 °C, 24 h, 79%; c) CH₃SO₂Cl, pyridine, 25 °C, 73%.

Scheme 4

Synthesis of C7-hydrogen-substituted THIQs. Reagents and conditions: a) ArCH₂Cl, Et₃N, EtOH, 130 °C, MW; b) ArCH₂Br, DIPEA, DMF, 80 °C; c) ArCO₂H, EDCI, Et₃N, CH₂Cl₂/THF, 25 °C; d) LiAlH₄, THF, 25 °C; e) ArCOCl, Et₃N, CH₂Cl₂, 25 °C; f) H₂, Pd/C, THF/MeOH, 25 °C, 1.5 h, 74%; g) H₂NSO₂Cl, DMA, 25 °C, 24 h, 88%.