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Synthesis, Antitubulin, and Antiproliferative SAR of C3/C1‐Substituted Tetrahydroisoquinolines
Author(s) -
Dohle Wolfgang,
Leese Mathew P.,
Jourdan Fabrice L.,
Major Meriel R.,
Bai Ruoli,
Hamel Ernest,
Ferrandis Eric,
Kasprzyk Philip G.,
Fiore Ann,
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.201300412
Subject(s) - tetrahydroisoquinoline , chemistry , stereochemistry , in vivo , tubulin , cancer cell , colchicine , cell culture , mechanism of action , methylation , microtubule , in vitro , cancer , biochemistry , biology , genetics , microbiology and biotechnology , gene
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 ( 6 b ), 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 ( 4 b ) against DU‐145 prostate cancer cells (GI 50 values: 220 n M and 2.1 μ M , respectively). Such compounds were also found to be active against a drug‐resistant 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.