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Carbon‐14 radiosynthesis of combretastatin A‐1 (CA1) and its corresponding phosphate prodrug (CA1P)
Author(s) -
Brown Rodney T.,
Murrell Victor L.,
McMordie Austin,
Sriram Madhavi,
Pinney Kevin G.,
Sharma Suman,
Chaplin David J.
Publication year - 2009
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.1676
Subject(s) - chemistry , prodrug , moiety , hydrolysis , trimethylsilyl , combretastatin , yield (engineering) , deoxyribose , phosphate , organic chemistry , methyl iodide , nuclear chemistry , medicinal chemistry , stereochemistry , nucleic acid , biochemistry , tubulin , microtubule , materials science , metallurgy , biology , microbiology and biotechnology
The natural product combretastatin A‐1 (CA1) is isolated from the African bush willow tree, a member of the Combretaceae family. CA1 has important medicinal value, due in part to its ability to inhibit tubulin assembly. The prodrug combretastatin A‐1 diphosphate (CA1P; OXi4503) is currently in human Phase I clinical trials as a vascular disrupting agent. This paper describes the carbon‐14 radiosynthesis of [4′‐ 14 C]CA1 and the corresponding phosphate prodrug salt [4′‐ 14 C]CA1P in high specific activity (55 mCi/mmol). The carbon‐14 label was introduced by methylation of the C‐4′ protected phenolic moiety of the CA1 precursor following removal of the tert ‐butyldimethylsilyl protecting group in the presence of [ 14 C]methyl iodide. This was accomplished in excellent yield without significant Z to E isomerization. The [ 14 C]‐precursor (( Z )‐1‐[3′,[4′‐ 14 C],5′‐trimethoxyphenyl]‐2‐[2″,3″‐di‐[( iso propyl)oxy]‐4″‐methoxyphenyl] ethene) was subjected to a de‐ iso propylation reaction with TiCl 4 . The tetrabenzyl phosphate derivative of the resulting diol was prepared using fresh dibenzyl phosphite. Debenzylation with trimethylsilylbromide, followed by hydrolysis of the trimethylsilyl ester and adjustment of the pH with dilute aqueous hydrochloric acid yielded [4′‐ 14 C]CA1P with an overall radiochemical yield of 8.4%. Copyright © 2009 John Wiley & Sons, Ltd.