title: Syntheses and evaluation of the antioxidant activity of acitretin analogs with amide bond(s) in the polyene spacer.
abstract: Ester analogs of the antipsoriatic drug acitretin were synthesized by coupling either anilines with N-protected indole-3-carboxylic acid, followed by deprotection and coupling with O-monoprotected dicarboxylic acids or Wittig reaction of indole-3-carboxaldehyde, 3-acetyl-1-tosylpyrrole and 4-amino-9-fluorenone with Ph3P=CHCO2tBu, followed by N-deprotection, where necessary, and finally coupling with cinnamoyl fluorides. Corresponding free acids were obtained through TFA-mediated carboxyl group deprotection. Although these analogs and acitretin showed very low reducing abilities, analogs 5, 6, 8 and 12 strongly inhibited LOX with IC50 values ranging from 35-65 microM. Acitretin and its analogs 5-7, 10, 11 and 15 inhibited lipid peroxidation more strongly than trolox whereas acitretin and analog 4 were in vivo more potent anti-inflammatory agents on rat paw oedema induced by Carrageenan than indomethacin.
authors: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. hadjipav@pharm.auth.gr
authors: Dimitra
authors: D
authors: Hadjipavlou-Litina
authors: George E
authors: GE
authors: Magoulas
authors: Marios
authors: M
authors: Krokidis
authors: Dionissios
authors: D
authors: Papaioannou
mesh_terms: D017255:Acitretin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000577:Amides / Q000737:chemistry*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D004583:Electrons; D004952:Esters / Q000737:chemistry; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007249:Inflammation / Q000188:drug therapy; D015227:Lipid Peroxidation / Q000187:drug effects; D008084:Lipoxygenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D011090:Polyenes / Q000737:chemistry*; D051381:Rats; D013025:Glycine max / Q000201:enzymology
chemical_list: D000577:Amides; D000975:Antioxidants; D004952:Esters; D006571:Heterocyclic Compounds; D016859:Lipoxygenase Inhibitors; D011090:Polyenes; D008084:Lipoxygenase; D017255:Acitretin