Trioxsalen derivatives with lipoxygenase inhibitory activity.
Trioxsalen (TRX) is a 4,5',8-trimethylated psoralen analog presenting interesting biological activities when irradiated with UVA light. A series of TRX derivatives, which where obtained by its chemical modification and incorporation of a variety of unsaturated functions at position 4' of the psoralen ring-system, were evaluated for their antioxidant activity and their inhibitory activity on soybean lipoxygenase (LOX) and lipid peroxidation. The reducing properties of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay and found to be very low, in the range 0-14%, with the exception of the hydroxamic acid 6 which showed almost identical activity to BHT. TRX derivative 3 significantly inhibited LOX, with IC(50) 9.4 muM. With the exception of TRX, all tested analogs inhibited lipid peroxidation in the range of 35-91%. The most potent compound, namely TRX derivative 3, was studied for its anti-inflammatory activity in vivo on rat paw edema induced by carrageenan, and was found to be of almost identical activity to indomethacin. The results of the biological tests are discussed in terms of structural characteristics.
Hadjipavlou-Litina
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Department of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece. hadjipav@pharm.auth.gr
E Bariamis
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Militsopoulou
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Athanassopoulos
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CM
Papaioannou
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D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000378:metabolism; D002351:Carrageenan / Q000737:chemistry; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism; D006614:Hindlimb; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008084:Lipoxygenase / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010851:Picrates / Q000378:metabolism; D051381:Rats; D013025:Glycine max / Q000201:enzymology; D014307:Trioxsalen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D016859:Lipoxygenase Inhibitors; D010851:Picrates; D002351:Carrageenan; C004931:1,1-diphenyl-2-picrylhydrazyl; D008084:Lipoxygenase; D007213:Indomethacin; D014307:Trioxsalen