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.

Abstract

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.

• Authors: Allyson L Anding, Nirca J Nieves, Victoria V Abzianidze, Michael D Collins, Robert W Curley Jr, Margaret Clagett-Dame
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 24 Issue 11 Pg. 1853-61 (Nov 21 2011) ISSN: 1520-5010 [Electronic] United States
• PMID: 21939267 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4-hydroxybenzylretinone
• Amides
• Antineoplastic Agents
• Benzoates
• DDIT3 protein, human
• Receptors, Retinoic Acid
• Retinoids
• Teratogens
• Vitamin A
• Transcription Factor CHOP
• Fenretinide
• Phenol
• 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid

Topics

• Administration, Oral
• Amides (chemistry)
• Animals
• 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)
• Female
• Fenretinide (chemical synthesis, therapeutic use)
• Humans
• Phenol (chemistry)
• Pregnancy
• Rats
• Rats, Sprague-Dawley
• Receptors, Retinoic Acid (metabolism)
• Retinoids (adverse effects, chemical synthesis, therapeutic use)
• Teratogens
• Transcription Factor CHOP (biosynthesis)
• Vitamin A (analogs & derivatives, chemical synthesis, therapeutic use)