Abstract 756: Optimization of tetrahydroisoquinoline-based microtubule disruptors as anticancer agents
Authors: Leese Mathew P. , Jourdan Fabrice L. , Ferrandis Eric , Regis-Lydi Sandra , Kasprzyk Philip G. , Fiore Ann , Newman Simon P. , Stengel Chloe , Reed Michael J. , Purohit Atul , Potter Barry VL 
Published: February 2011

Abstract
We outline the discovery and optimisation of new microtubule disruptors with in vivo anti-tumor activity. Translation of the SAR from a steroidal series of microtubule disruptors led us to identify a series of tetrahydroisoquinoline (THIQ) based systems which exhibit a similar activity profile. Of this new series, 2-(3′,4′,5′-Trimethoxybenzyl)-7-methoxy-6-O-sulfamoyl THIQ 1 proved especially potent in both in vitro (GI50 [DU-145] 297 nM) and in vivo experiments. Herein, we describe the results of optimisation at C-6 and C-7 of the THIQ core and assessment of other polymethoxylated N-benzyl systems.
Variations at the N-2 and C-6 positions were achieved by alkylation, esterification and etherification. Friedel Crafts acylation of C-7 and functional group interconversion allowed access to various C-7 alkyl and alkoxy derivatives. The various dimethoxybenzyl compounds proved similar in activity to the lead compound 2 (GI50 2.1 μM) in the N-mono-methoxybenzyl series while, apart from the 3′,4′,5′-trimethoxybenzyl compound 1, only 2′,4′,5′-trimethoxybenzyl substitution delivered sub-micromolar activity. Investigations of the effect of C-6 substitution proved more fruitful. In contrast to the SAR observed for 2 where the sulfamate group is essential for activity, the 6-OH, with the 6-O-acyl and 6-O-mesyl derivatives of 1 displayed similar or improved activity to the parent compound (GI50s range from 650 to 220 nM). The 6-O-methyl derivative, in contrast, proved completely inactive, highlighting the importance of a H-bond donor directly attached to C-6 or a H-bond acceptor projecting further out from this position. The most pronounced improvement in activity was obtained from exploration of C-7 substitution. In the 3′,4′,5′-trimethoxybenzyl series isosteric replacement of methoxy with ethyl delivered a 7-fold improvement in activity (3 GI50 41 nM). Intriguingly, the corresponding phenol proved significantly active suggesting different binding modes operate for the phenol and sulfamate derivatives since the H-bond acceptor properties of the C-7 substituent of the former are clearly important. Incorporation of a C-7 ethoxy group meanwhile proved detrimental for both sulfamate and phenol derivatives. The same transformations were made to 2, though no improvement in activity was obtained.
In order to establish the potential of these compounds as anti-tumor agents their activity in the RPMI-8226 multiple myeloma xenograft model was assessed. The &gt;75% inhibition of tumor growth observed (3 p.o. 40 mg/kg, 28d) in this preliminary study augers well for the development of this class of anti-cancer agents.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 756.