Syntheses and evaluation of the antioxidant activity of acitretin analogs with amide bond(s) in the polyene spacer.
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.
Hadjipavlou-Litina
Dimitra
D
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. hadjipav@pharm.auth.gr
Magoulas
George E
GE
Krokidis
Marios
M
Papaioannou
Dionissios
D
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
D000577:Amides; D000975:Antioxidants; D004952:Esters; D006571:Heterocyclic Compounds; D016859:Lipoxygenase Inhibitors; D011090:Polyenes; D008084:Lipoxygenase; D017255:Acitretin