Origin and Cytotoxic Properties of Base Propenals Derived from DNA

Base propenals arise from DNA by a Fe(ll)-bleomycin-mediated reaction which leads to strand scission. These compounds undergo addition-elimination reactions with thiols and other nu-cleophilic groups under physiological conditions and form an addition product with glutathione. Thymine- and adenine-N¹-propenals inhibit DNA synthesis in HeLa cells; both compounds are cytotoxic [50% inhibiting concentration (IC50) = 1 to 2 μM]. A structurally related nucleoside, thymidine-N³-propenal, designed as a metabolic pathway inhibitor, inhibits growth of HeLa, L1210 leukemia, Lewis lung carcinoma, B16 melanoma, and DLD-1 human colon carcinoma cells in culture (IC50 = 1 to 6 μM). A single injection of this compound, administered on the first day following transplant of L1210 leukemia cells, increased the mean survival time of mice by 50% (T/C = 154). Thymidine-N³-propenal selectively blocks DNA synthesis in HeLa cells and inhibits thymidine kinase (Kj = 5.1 μM) and DNA polymerase-α. We suggest that base propenals, rather than damaged DNA, account for some of the cytotoxic effects of bleomycin and that nucleoside propenals represent a novel class of site-directed inhibitors.