Trioxsalen derivatives with lipoxygenase inhibitory activity

Abstract

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 IC₅₀ 9.4 μM. 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.

Keywords::

• Psoralens
• trioxsalen
• trioxsalen derivatives
• antioxidant activities
• anti-inflammatory activities
• lipoxygenase inhibitors
• lipid peroxidation

Acknowledgements

We thank the European Social Fund (ESF) Operational Programme for Educational and Vocational Training II (EPEAEK II) and particularly the Program PYTHAGORAS II for funding the synthetic part of this work. We would also like to thank Dr. C. Hansch and Biobyte Corp., Claremont, CA, USA for free access to the C-QSAR program.

A part of this research has been presented at the 13th Panhellenic Symposium of Pharmacochemistry, 2008.

Declaration of interest: The authors report no conflicts of interest.