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4-Hydroxybenzyl Modification of the Highly Teratogenic Retinoid, 4-[(1E)-2-(5, 5, 8, 8-Tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthalenyl)-1-propen-1-yl]benzoic acid (TTNPB), Yields a Compound that Induces Apoptosis in Breast Cancer Cells and Shows Reduced Teratogenicity.
MedLine Citation:
PMID:  21939267     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Retinoids are a class of compounds with structural similarity to vitamin A. These compounds inhibit the proliferation of many cancer cell lines but have had limited medical application as they are often toxic at therapeutic levels. Efforts to synthesize retinoids with a greater therapeutic index have met with limited success. 4-[(1E)-2-(5, 5, 8, 8-Tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthalenyl)-1-propen-1-yl]benzoic acid (TTNPB1) is one of the most biologically active all-trans-retinoic acid (atRA) analogs and is highly teratogenic. In this study, we show that modification of the TTNPB carboxyl group with an N-(4-hydroxyphenyl)amido (4HPTTNPB) or a 4-hydroxybenzyl (4HBTTNPB) group changes the activity of the compound in cell culture and in vivo. Unlike TTNPB, both compounds induce apoptosis in cancer cells and bind poorly to the retinoic acid receptors (RARs). Like the similarly modified all-trans-retinoic acid (atRA) analogs N-(4-hydroxyphenyl)retinamide (4-HPR / fenretinide) and 4-hydroxybenzylretinone (4-HBR), 4HBTTNPB is a potent activator of components of the ER stress pathway. The amide-linked analog, 4HPTTNPB, is less toxic to developing embryos than the parent TTNPB, and most significantly, the 4-hydroxybenzyl-modified compound (4HBTTNPB) that cannot be hydrolyzed in vivo to the parent TTNPB compound is nearly devoid of teratogenic liability.
Authors:
Allyson L Anding; Nirca J Nieves; Victoria V Abzianidze; Michael D Collins; Robert William Curley; Margaret Clagett-Dame
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-9-22
Journal Detail:
Title:  Chemical research in toxicology     Volume:  -     ISSN:  1520-5010     ISO Abbreviation:  -     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-9-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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