Methylenebisphosponic acid tetraethyl ester (1) was added to 2-azido-7a-e and 2-chloroquinoline-3-chalcones 10a-e in boiling sodium ethanolate solution to give, via Michael addition, tetrazolo[1,5-a]quinoline-8a-d, 13a and 2-chloroquinoline-based bisphosphonates 11a-d, 14a in E-configuration. Further acid hydrolysis afforded the respective BP-acid analogues E-9a-d, 12a-d, 13b, and 14b in excellent yields. Anti-tumor activity screening for the new BP-acids at a dose of 10 µM utilizing 44 different human tumor cell lines representing breast, ovary, prostate, lung, and CNS cancer as well as leukemia and melanoma was carried out. Eight of ten tested compounds exhibited remarkable anti-tumor activity against breast and prostate cancer, and a promising anti-tumor sensitivity toward ovarian cancer and melanoma. Conversely, there was only scattered activity against leukemia and no noticeable action of these BP-acids on CNS or lung cancer. Based on the prediction results (PASS program), anti-inflammatory activity of the new acids was also determined in vivo, by the acute carrageenin induced paw edema in rats. Many of these compounds showed anti-inflammatory properties at a dose of 50 mg/kg body weight.
A series of the title compounds, 9-deazaxanthines, was regioselectively prepared in reasonable yields as major products from the reactions of 6-azidouracils 1a,b with stabilized ester-2a,b or keto-2c ylide phosphoranes and a moderated phosphorus ylide 3, instead of the expected triazoles. Side products were also observed wherein pyrimido [5,4-g]pteridine-2,4,5,7-tetrone (15) and other fused ring systems or acyclic-substituted uracil derivatives were isolated. A comparative study on the reactivity of 1a in analogy to 1b toward phosphoranes is also described.
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