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Dohle W.,University of Bath | Leese M.P.,University of Bath | Jourdan F.L.,University of Bath | Major M.R.,University of Bath | And 8 more authors.
ChemMedChem | Year: 2014

The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl-substituted sulfamate ()- 7-methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy- 1,2,3,4- tetrahydroisoquinoline (6b), for example, was found to be ~10-fold more potent than the corresponding non-methylated compound 7-methoxy-2-(3-methoxybenzyl)-6- sulfamoyloxy- 1,2,3,4-tetrahydroisoquinoline (4b) against DU-145 prostate cancer cells (GI50 values: 220 nm and 2.1 mm, respectively). Such compounds were also found to be active against a drugresistant MCF breast cancer cell line. The position and nature of substitution of the N-benzyl group in the C3-substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3-gem-dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study. © 2014 Wiley-VCH Verlag GmbH and Co. Source


Leese M.P.,University of Bath | Jourdan F.L.,University of Bath | Major M.R.,University of Bath | Dohle W.,University of Bath | And 5 more authors.
ChemMedChem | Year: 2014

A structure-activity relationship (SAR) translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)-based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B-ring-mimicking THIQ core was connected to methoxyaryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g., 7-methoxy-2-(3- methoxybenzyl)-6-sulfamoyloxy-1,2,3, 4-tetrahydroisoquinoline (20 c) GI50=2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ-based A,B-mimic with the trimethoxyaryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (GI50=40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 7-methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4- tetrahydroisoquinoline (20 z) relative to a benchmark steroidal bis- sulfamate Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Dohle W.,University of Bath | Leese M.P.,University of Bath | Jourdan F.L.,University of Bath | Chapman C.J.,University of Bath | And 3 more authors.
ChemMedChem | Year: 2014

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=1.6 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. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Leese M.P.,University of Bath | Jourdan F.L.,University of Bath | Major M.R.,University of Bath | Dohle W.,University of Bath | And 7 more authors.
ChemMedChem | Year: 2014

A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)-based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)-based compounds. A steroid A,B-ring-mimicking DHIQ core was connected to methoxyaryl D-ring mimics through methylene, carbonyl, and sulfonyl linkers, and the resulting compounds were evaluated against two cancer cell lines. The carbonyl-linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H) -one (16 g): GI50 51 nM in DU-145 cells). The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60-cell line assay giving a mean activity of 33 nM. Furthermore, 6-hydroxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3, 4-dihydroisoquinolin-1(2H)-one (16 f) and 16 g and their sulfamate derivatives 17 f and 17 g (2-(3,5-dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4- dihydroisoquinolin-1(2H)-one and 7-methoxy-2-(3,4,5-trimethoxybenzoyl)-6- sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one, respectively) show excellent activity against the polymerization of tubulin, close to that of the clinical combretastatin A-4, and bind competitively at the colchicine binding site of tubulin. Compounds 16 f and 17 f were also shown to demonstrate in vitro anti-angiogenic activity. Additionally, X-ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a "steroid- like" conformation that may partially explain the excellent in vitro activities. Steroid-oids: Steroidomimetic dihydroisoquinolinones (DHIQs) were evaluated against two cancer cell lines. Carbonyl-linked DHIQs exhibit significant in vitro antiproliferative activity, show excellent activity against tubulin polymerisation, and compete at the colchicine binding site of tubulin. Crystal structure analysis and molecular modelling both suggest a preferred "steroid-like" conformation as a result of intramolecular electrostatic repulsion for this compound class. © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Source


Jourdan F.,University of Bath | Leese M.P.,University of Bath | Dohle W.,University of Bath | Ferrandis E.,Institute Of Recherche Henri Beaufour | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2011

The synthesis and antiproliferative activities of analogues of 2-substituted estradiol-3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent confirm that an H-bond acceptor is essential for high activity; its optimal linkage to C-17 and the local environment in which it resides are defined. In the non-sulfamoylated series 17β-acyl substitution delivers 48b, the most potent compound identified to date. In the sulfamate series a number of permutations of linker and H-bond acceptor deliver excellent activity, with 55, 61, 65, 49a, and 49b proving especially promising. The in vivo potential of these compounds was explored in the NCI hollow fiber assay and also in a mouse Matrigel model of antiangiogenesis in which 49 and 55 show significant inhibitory activity. © 2011 American Chemical Society. Source

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