Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers

J Med Chem. 1997 Dec 19;40(26):4222-34. doi: 10.1021/jm9704309.

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.

MeSH terms

  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / metabolism
  • Azepines / 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
  • Retinoids / antagonists & inhibitors
  • Retinoids / metabolism
  • Retinoids / pharmacology*
  • Tetrahydronaphthalenes / pharmacology
  • Transcription Factors / metabolism*

Substances

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