Synthesis, anti-tubulin and antiproliferative SAR of steroidomimetic dihydroisoquinolinones

Mathew P. Leese, Fabrice L. Jourdan, Meriel R. Major, Wolfgang Dohle, Mark P. Thomas, Ernest Hamel, Eric Ferrandis, Mary F. Mahon, Simon P. Newman, Atul Purohit, Barry V. L. Potter

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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 (16g): GI 51nM in DU-145 cells). The broad anticancer activity of DHIQ 16g was confirmed in the NCI 60-cell line assay giving a mean activity of 33nM. Furthermore, 6-hydroxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (16f) and 16g and their sulfamate derivatives 17f and 17g (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 16f and 17f were also shown to demonstrate in vitro anti-angiogenic activity. Additionally, X-ray and computational analyses of 17f 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.
Original languageEnglish
Pages (from-to)798-812
JournalChemMedChem
Volume9
Issue number4
Early online date5 Mar 2014
DOIs
Publication statusPublished - Apr 2014

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