title: Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
abstract: In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Umemiya
authors.forename: H
authors.initials: H
authors.lastname: Fukasawa
authors.forename: M
authors.initials: M
authors.lastname: Ebisawa
authors.forename: L
authors.initials: L
authors.lastname: Eyrolles
authors.forename: E
authors.initials: E
authors.lastname: Kawachi
authors.forename: G
authors.initials: G
authors.lastname: Eisenmann
authors.forename: H
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Shudo
authors.forename: H
authors.initials: H
authors.lastname: Kagechika
mesh_terms: D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects; D003984:Dibenzazepines / Q000494:pharmacology; D019281:Dimerization; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001381:Azepines; D001565:Benzoates; D003984:Dibenzazepines; C104182:LE 135; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C061133:tamibarotene