title: Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
abstract: Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.
authors.affiliation: Department of Obstetrics & Gynecology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, Oklahoma 73190, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dhar
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Klucik
authors.forename: K D
authors.initials: KD
authors.lastname: Berlin
authors.forename: M M
authors.initials: MM
authors.lastname: Madler
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.forename: R T
authors.initials: RT
authors.lastname: Ivey
authors.forename: D
authors.initials: D
authors.lastname: Zacheis
authors.forename: C W
authors.initials: CW
authors.lastname: Brown
authors.forename: E C
authors.initials: EC
authors.lastname: Nelson
authors.forename: P J
authors.initials: PJ
authors.lastname: Birckbichler
authors.forename: D M
authors.initials: DM
authors.lastname: Benbrook
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D011804:Quinolines; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D011503:Transglutaminases; D000097768:Retinoic Acid Receptor gamma