Synthesis and Biological Activity of Azido Analogues of 5,6-dimethylxanthenone-4-acetic Acid for Use in Photoaffinity Labeling.
From: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Journal of medicinal chemistry
- Publish Date: Aug 2007
- ISSN: 0022-2623
- Volume: 50
- Issue: 16
- Pages: 3757-64
- Medium: Print
- Language: English
- Citation (JAMA): Palmer Brian D, Henare Kimiora, Woon See-Tarn, et al. Synthesis and Biological Activity of Azido Analogues of 5,6-dimethylxanthenone-4-acetic Acid for Use in Photoaffinity Labeling.. J. Med. Chem. Aug 2007;50:3757-64
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.
Mesh Headings (Keywords): Adenocarcinoma, Animals, Antineoplastic Agents, Azides, Cells, Cultured, Colonic Neoplasms, Hemorrhage, Mice, Mice, Inbred C57BL, NF-kappa B, Necrosis, Photoaffinity Labels, Protein Binding, Spleen, Structure-Activity Relationship, Transplantation, Heterologous, Tumor Necrosis Factor-alpha, Xanthones
Check for Full Text / PubMed Unique Identifier (PMID): 17616114
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