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Synthesis, Anti‐tubulin and Antiproliferative SAR of Steroidomimetic Dihydroisoquinolinones
Author(s) -
Leese Mathew P.,
Jourdan Fabrice L.,
Major Meriel R.,
Dohle Wolfgang,
Thomas Mark P.,
Hamel Ernest,
Ferrandis Eric,
Mahon Mary F.,
Newman Simon P.,
Purohit Atul,
Potter Barry V. L.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201400017
Subject(s) - tubulin , chemistry , in vitro , stereochemistry , microtubule , ring (chemistry) , methylene , combretastatin , cell culture , colchicine , sulfonyl , biochemistry , biology , medicinal chemistry , alkyl , genetics , organic chemistry , microbiology and biotechnology
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(2 H )‐one ( 16 g ): GI 50 51 n M 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 n M . Furthermore, 6‐hydroxy‐2‐(3,5‐dimethoxybenzoyl)‐7‐methoxy‐3,4‐dihydroisoquinolin‐1(2 H )‐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(2 H )‐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.