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 12e,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 20b 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 = 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.

Targeted NF1 cancer therapeutics with multiple modes of action: small molecule hormone-like agents resembling the natural anticancer metabolite, 2-methoxyoestradiol

“…In a cell-free system, STX3451 has been shown to inhibit tubulin assembly and block colchicine binding to tubulin ( Dohle et al , 2014 ). Colchicine binds to β -tubulin and interferes with polymerisation of tubulin molecules to form microtubules ( Luduena and Roach, 1991 ).…”

“…STX2484, STX2895 and STX3451 were synthesised as described ( Leese et al , 2010 ; Dohle et al , 2014 ). The compounds exhibited spectroscopic and analytical data in accordance with their structures ( Figure 1A ) and were pure, as determined by high-performance liquid chromatography.…”

“…Although 2ME2 appears to have a modest pharmacokinetic profile ( Bruce et al , 2012 ), sulfamoylated variants of 2ME2 including the ‘bisMATEs', 2ME2-3,17- O,O -bis-sulphamate (2ME2bisMATE, STX140) its close analogue STX243 ( Leese et al , 2006 ; Newman et al , 2008 ) as well as STX641 and non-steroidal sulphamate derivatives ( Leese et al , 2010 ; Dohle et al , 2014 ; Stengel et al , 2014 ) exhibited therapeutic properties that were significantly improved relative to 2ME2. 2-methoxyoestrone-3- O -sulphamate inhibits taxol-stimulated tubulin polymerization ( MacCarthy-Morrogh et al , 2000 ), and two 3,17- O , O -bissulfamates STX140 and STX243 inhibit tubulin polymerization by targeting the colchicine-binding site on tubulin ( Stengel et al , 2010 ).…”

“…In combination, 2-MEbisMATE (STX140) and 2-deoxyglucose exhibit synergy in reducing tumour volume and STX140 may sensitise tumours to inhibition of glycolysis ( Tagg et al , 2008 ). Another novel 2ME2 variant, STX3451 (2-(3-Bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline; Figure 1A ), is a non-steroidal tetrahydroisoquinoline sulphamate derivative that displays high anti-proliferative activity across the NCI 60 cell line panel (average GI 50 50 n M ; Dohle et al , 2014 ). The ability of STX3451, like STX140, to disrupt normal microtubule dynamics through binding to the colchicine site in a cell-free system appears to make a significant contribution to this compound's anti-proliferative effects ( Dohle et al , 2014 ).…”

EDL-360: A Potential Novel Antiglioma Agent

“…Several groups reported cytotoxic activity of different THIQ derivatives against numerous cancer types including retinoblastoma, squamous call carcinoma, lung cancer cells and breast cancer [ 16 – 20 ]. The antiproliferative properties of THIQ may in part reflect its ability to inhibit microtubule polymerization [ 21 – 23 ]. Our data suggests that EDL-360 induced cell death via an apoptotic pathway in glioma cells as measured by the accumulation of sub-G1 population ( Figure 1 ).…”