Document Detail

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:  MEDLINE    
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 (TTNPB) is one of the most biologically active all-trans-retinoic acid (atRA) analogues 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) analogues 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 analogue, 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.
Allyson L Anding; Nirca J Nieves; Victoria V Abzianidze; Michael D Collins; Robert W Curley; Margaret Clagett-Dame
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-19
Journal Detail:
Title:  Chemical research in toxicology     Volume:  24     ISSN:  1520-5010     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-21     Completed Date:  2012-04-02     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1853-61     Citation Subset:  IM    
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MeSH Terms
Administration, Oral
Amides / chemistry
Antineoplastic Agents / adverse effects,  chemical synthesis*,  therapeutic use
Apoptosis / drug effects
Benzoates / adverse effects,  chemical synthesis*,  therapeutic use
Binding, Competitive
Breast Neoplasms / drug therapy*,  pathology
Cell Division / drug effects
Cell Line, Tumor
Endoplasmic Reticulum / drug effects*,  metabolism
Fenretinide / chemical synthesis,  therapeutic use*
Phenol / chemistry
Rats, Sprague-Dawley
Receptors, Retinoic Acid / metabolism*
Retinoids / adverse effects,  chemical synthesis*,  therapeutic use
Transcription Factor CHOP / biosynthesis
Vitamin A / analogs & derivatives*,  chemical synthesis,  therapeutic use
Grant Support
Reg. No./Substance:
0/4-hydroxybenzylretinone; 0/Amides; 0/Antineoplastic Agents; 0/Benzoates; 0/DDIT3 protein, human; 0/Receptors, Retinoic Acid; 0/Retinoids; 0/Teratogens; 11103-57-4/Vitamin A; 147336-12-7/Transcription Factor CHOP; 187EJ7QEXL/Fenretinide; 339NCG44TV/Phenol; 71441-28-6/4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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