title: 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.affiliation: Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Allyson L
authors.initials: AL
authors.lastname: Anding
authors.forename: Nirca J
authors.initials: NJ
authors.lastname: Nieves
authors.forename: Victoria V
authors.initials: VV
authors.lastname: Abzianidze
authors.forename: Michael D
authors.initials: MD
authors.lastname: Collins
authors.forename: Robert W
authors.initials: RW
authors.lastname: Curley
authors.forename: Margaret
authors.initials: M
authors.lastname: Clagett-Dame
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D017313:Fenretinide / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D019800:Phenol / Q000737:chemistry; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D013723:Teratogens; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use
chemical_list: C451736:4-hydroxybenzylretinone; D000577:Amides; D000970:Antineoplastic Agents; D001565:Benzoates; C497249:DDIT3 protein, human; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013723:Teratogens; D014801:Vitamin A; D051742:Transcription Factor CHOP; D017313:Fenretinide; D019800:Phenol; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid