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ChemMedChem. 2014 Jan;9(1):85-108, 1. doi: 10.1002/cmdc.201300261. Epub 2013 Oct 9.

Tetrahydroisoquinolinone-based steroidomimetic and chimeric microtubule disruptors.

Author information

1
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY (UK).

Abstract

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 relative to a benchmark steroidal bis- sulfamate in an in vivo model of multiple myeloma.

KEYWORDS:

colchicine binding; microtubule disruptors; tetrahydroisoquinolines; tubulin assembly

PMID:
24124095
PMCID:
PMC3877212
DOI:
10.1002/cmdc.201300261
[Indexed for MEDLINE]
Free PMC Article

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