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: H Umemiya, H Fukasawa, M Ebisawa, L Eyrolles, E Kawachi, G Eisenmann, H Gronemeyer, Y Hashimoto, K Shudo, H Kagechika
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 40 Issue 26 Pg. 4222-34 (Dec 19 1997) ISSN: 0022-2623 [Print] United States
• PMID: 9435893 (Publication Type: Journal Article)

Chemical References

• Azepines
• Benzoates
• Dibenzazepines
• LE 135
• Receptors, Retinoic Acid
• Retinoid X Receptors
• Retinoids
• Tetrahydronaphthalenes
• Transcription Factors
• tamibarotene

Topics

• Azepines (chemical synthesis, chemistry, metabolism, pharmacology)
• Benzoates (pharmacology)
• Binding, Competitive
• Cell Differentiation (drug effects)
• Dibenzazepines (pharmacology)
• Dimerization
• Drug Synergism
• HL-60 Cells
• Humans
• Molecular Structure
• Protein Binding
• Receptors, Retinoic Acid (metabolism)
• Retinoid X Receptors
• Retinoids (agonists, antagonists & inhibitors, metabolism, pharmacology)
• Tetrahydronaphthalenes (pharmacology)
• Transcription Factors (metabolism)