City of Hope

Lawrence C Sowers

Kevin J Scanlon

A synthesis of 5-fluoro-2'-ideoxycytidine, of oligonucleotides containing 5-fluoro-2'-deoxycytidine and of certain novel 4-alkoxy-5-fluoro-2'-deoxyuridines is disclosed. These 4-alkoxy compounds are useful intermediates for the preparation of other 4-substituted, 5-fluoro pyrimidine deoxynucleosides, and spontaneously hydrolyze in target cells to form FdU and derivatives thereof.

Synthesis of 4-alkoxy-5-fluoro-2'-deoxyuridine and its incorporation

A method involving the administration of nucleoside analogs to circumvent resistance attributable to the enhanced DNA repair capacity of cancer cells is described. The nucleoside analogs function as suicide substrates for DNA repair enzymes. A method of screening nucleoside analogs for utility as antitumor agents and a screening assay to individual recurrent tumors is described.

Circumvention of human tumor drug resistance

4-Ethoxy-5-fluoro-2'-deoxyuridine is disclosed as an intermediate in the synthesis of 5'-fluoro-2'-deoxycytidine. The treatment of 4-ethoxy-5-fluoro-2'-deoxyuridine with methanolic ammonia eliminates the side product of 5-fluoro-2'-deoxyuridine which occurs when 4-methoxy-5-fluoro-2'-deoxyuridine is used as the reactant. 4-Ethoxy-5-fluoro-2'-deoxyuridine is also a prodrug of 5-fluoro-2'-deoxyuridine which is substantially less toxic than parent free nucleoside 5-fluoro-2'-deoxyuridine.

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Duarte, CA, United States of America

Lawrence C Sowers