Synthesis and biological activity of a new class of cytotoxic agents: N-(3-oxoprop-1-enyl)-substituted pyrimidines and purines.
The 1-(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-1-enyl) derivatives of thymidine, 2'-deoxyuridine, and 5-iodo-2'-deoxyuridine powerfully and selectively inhibit incorporation of thymidine into DNA at concentrations (IC50 approximately equal to 0.5 microM) 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.
D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D006367:HeLa Cells / Q000166:cytology; D006801:Humans; D014176:Protein Biosynthesis; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D000447:Aldehydes; D000970:Antineoplastic Agents; D011687:Purines; D011743:Pyrimidines; D012313:RNA