Synthesis, Antitubulin, and Antiproliferative SAR of C3/C1-Substituted Tetrahydroisoquinolines
| Autor: | Ernest Hamel, Ann Fiore, Simon P. Newman, Ruoli Bai, Mathew P. Leese, Meriel R. Major, Fabrice Jourdan, Philip G. Kasprzyk, Wolfgang Dohle, Eric Ferrandis, Atul Purohit, Barry V. L. Potter |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Stereochemistry Mice Nude Antineoplastic Agents Biochemistry Mice Structure-Activity Relationship chemistry.chemical_compound Prostate cancer Tubulin In vivo Microtubule Cell Line Tumor Neoplasms Tetrahydroisoquinolines Drug Discovery medicine Animals Humans Colchicine General Pharmacology Toxicology and Pharmaceutics Cell Proliferation Pharmacology biology Tetrahydroisoquinoline Organic Chemistry Stereoisomerism Methylation medicine.disease Tubulin Modulators Mechanism of action chemistry biology.protein Molecular Medicine Female medicine.symptom Multiple Myeloma |
| Zdroj: | ChemMedChem. 9:350-370 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201300412 |
| Popis: | 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 (6b), 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 (4b) against DU-145 prostate cancer cells (GI values: 220nM and 2.1μM, 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. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
| Databáze: | OpenAIRE |
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