Synthesis and Biological Activity of a New Class of Cytotoxic Agents: N-(3-Oxoprop-l-enyl)-Substituted Pyrimidines and Purines

The l-(3-oxoprop-1-enyl) derivatives of thymine and cytosine and the corresponding 9-substituted derivatives of adenine and guanine (products of degradation of DNA by bleomycin, Fe²⁺, and O₂) have been synthesized and tested for biological activity. The thymine and adenine compounds are highly cytotoxic to a variety of tumor cell lines and inhibit macromolecular synthesis in cultured HeLa cells. Structure-activity studies, based primarily on the pyrimidine derivatives, reveal that the most potent inhibition occurs when the propenal group is located on the 3-nitrogen of a 2'-deoxyribonucleoside. The 3-(3-oxoprop-l-enyl) derivatives of thymidine, 2'-deoxyuridine, and 5-iodo-2'-deoxyuridine powerfully and selectively inhibit incorporation of thymidine into DNA at concentrations (1C₅₀ ≈ 0.5 μM) comparable to those observed with idoxuridine. Active compounds in this series react readily with nucleophiles containing primary amino and sulfhydryl groups. The results of this study provide a basis for the development of a new class of cytotoxic agents.