| Abstract: |
The pyridopyrimidinones are a potent class of inhibitors of c-Abl kinase and Bcr-Abl kinase, the causative fusion protein in chronic myelogenous leukemia and Src family kinases. A novel method for routine, high-yield no-carrier-added synthesis of [124I]-, [125I]- and [131I]-6-(2, 6-dichlorophenyl)-2-(4-iodophenylamino)-8-methyl-8H-pyrido[2,3-d] pyrimidin-7-one has been developed. The 4′-trimethylstannyl- or 4′-tri-n-butylstannyl-pyridopyrimidinone precursors were prepared from the aryl bromide via a palladium-mediated coupling with hexaalkylditin (dioxane/microwave irradiation/10 min at 160°C). The radioiodination of 4′-stannylpyridopyrimidinones was found to optimally occur via an iododestannylation with Na124I, Na125I or Na 131I in the presence of an oxidant [30% H2O 2/HOAc (1:3)/10 min] in 79-87% radiochemical yield with >99% radiochemical purity. The total radiosynthesis time was 30 min. The 4-iodophenylpyridopyrimidinone 2 inhibited recombinant Abl kinase activity with an IC50 of 2.0 nM. Cell proliferation of K562 and A431 cells was inhibited with an IC50 of 2.0 and 20 nM, respectively. Rapid cellular uptake and equilibrium were observed within 10-15 min using [ 131I]-4-iodophenylpyridopyrimidinone 6c in K562 and A431 cells and demonstrated a 2.8-fold uptake selectivity for the Bcr-Abl-expressing K562 cells at 60 min. These results suggest that pyridopyrimidinone radiotracers may be useful in imaging Abl-, Bcr-Abl- or Src-expressing malignancies. © 2005 Elsevier Inc. All rights reserved. |
| Keywords: |
controlled study; unclassified drug; human cell; carcinoma, squamous cell; radiopharmaceuticals; cell proliferation; cell survival; dose-response relationship, drug; enzyme activity; cell line, tumor; pyrimidinone derivative; drug synthesis; pyrimidines; cancer inhibition; drug uptake; isotope labeling; iodine radioisotopes; radiopharmaceutical agent; metabolic clearance rate; protein-tyrosine kinases; hydrogen peroxide; tyrosine kinase inhibitor; ic 50; acetic acid; phosphotransferase inhibitor; palladium; growth inhibition; microwave radiation; radioiodination; leukemia, myeloid, chronic; iodine-125; iodine-124; iodine-131; iododestannylation; pyridopyrimidinone; 4 iodophenylpyridopyrimidinone; 4 iodophenylpyridopyrimidinone i 131; 4' tri n butylstannylpyridopyrimidinone; 4' trimethylstannylpyridopyrimidinone; 6 (2,6 dichlorophenyl) 2 (4 iodophenylamino) 8 methyl 8h pyrido[2,3 d]pyrimidin 7 one i 124; 6 (2,6 dichlorophenyl) 2 (4 iodophenylamino) 8 methyl 8h pyrido[2,3 d]pyrimidin 7 one i 125; 6 (2,6 dichlorophenyl) 2 (4 iodophenylamino) 8 methyl 8h pyrido[2,3 d]pyrimidin 7 one i 131; abelson kinase inhibitor; bromide; dioxane
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