Synthesis and biological activity of azido analogues of 5,6-dimethylxanthenone-4-acetic acid for use in photoaffinity labeling.
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.
Palmer
Brian D
BD
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Henare
Kimiora
K
Woon
See-Tarn
ST
Sutherland
Rachel
R
Reddy
Charu
C
Wang
Liang-Chuan S
LC
Kieda
Claudine
C
Ching
Lai-Ming
LM
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D006470:Hemorrhage / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D044004:Xanthones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C524099:5-azido-6-methylxanthenone-4-acetic acid; C524098:5-azidoxanthenone-4-acetic acid; D000970:Antineoplastic Agents; D001386:Azides; D016328:NF-kappa B; D019920:Photoaffinity Labels; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C066668:vadimezan