title: Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.
abstract: Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.
authors.affiliation: Department of Chemistry, Allergan, Incorporated, Irvine, California 92715-1599, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Beard
authors.forename: R A
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: D F
authors.initials: DF
authors.lastname: Colon
authors.forename: S J
authors.initials: SJ
authors.lastname: Gillett
authors.forename: E
authors.initials: E
authors.lastname: Henry
authors.forename: D K
authors.initials: DK
authors.lastname: Marler
authors.forename: T
authors.initials: T
authors.lastname: Song
authors.forename: L
authors.initials: L
authors.lastname: Denys
authors.forename: M E
authors.initials: ME
authors.lastname: Garst
authors.forename: T
authors.initials: T
authors.lastname: Arefieg
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D013267:Stilbenes; D014157:Transcription Factors; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid