Synthesis and Biological Activity of Azido Analogues of 5,6-Dimethylxanthenone-4-acetic Acid for Use in Photoaffinity Labeling

Abstract : 5,6-Dimethylxanthenone-4-acetic acid (1) is scheduled for phase III clinical trials as a vascular disrupting agent. However, its biochemical receptor(s) have yet to be identified. In this report, the synthesis of azido analogues of 1 that could be used for photoaffinity labeling of proteins as an approach toward identifying its molecular targets is described. While 5-azidoxanthenone-4-acetic acid (2) and 5-azido-6-methylxantheone-4-acetic acid (3) were found to have biological activities similar to that of 1, 6-azido-5-methylxanthenone-4-acetic acid (4) was unstable and could not be evaluated. Both azido compounds 2 and 3 activated NF-kappaB, induced the production of tumor necrosis factor in cultured mouse splenocytes, and induced hemorrhagic necrosis of colon 38 tumors in mice. Photoreaction of lysates from spleen cells with tritiated 2 resulted in two radiolabeled protein bands at 50 and 14 kDa that could be competitively inhibited with cold 1 and cold 2. The azido compounds 2 and 3 exhibit all the requirements for use in photoaffinity labeling of potential receptor(s) for 1.
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https://hal.archives-ouvertes.fr/hal-00166542
Contributor : Isabelle Frapart <>
Submitted on : Tuesday, August 7, 2007 - 10:53:43 AM
Last modification on : Wednesday, June 27, 2018 - 8:24:02 AM

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Brian D. Palmer, Kimiora Henare, See-Tarn Woon, Rachel Sutherland, Charu Reddy, et al.. Synthesis and Biological Activity of Azido Analogues of 5,6-Dimethylxanthenone-4-acetic Acid for Use in Photoaffinity Labeling. Journal of Medicinal Chemistry, American Chemical Society, 2007, 50 (16), pp.3757-3764. ⟨10.1021/jm0702175 S0022-2623(07)00217-8⟩. ⟨hal-00166542⟩

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