Inhibition of cellular thymidylate synthesis by cytotoxic propenal derivatives of pyrimidine bases and deoxynucleosides

A series of cytotoxic propenal (3-oxoprop-1-enyl) derivatives of pyrimidine bases and deoxynucleosides was evaluated for their ability to block thymidylate synthesis in intact and permeabilized murine leukemia L1210 cells. Several were potent inhibitors of this process, likely contributing to their cytotxicity. The IC₅₀ values of thymidine-3-propenal, the prototype of this series, in intact and permeabilized L1210, L-M and L-M(TK^-) cells were 21, 7.5, and 75 μM and 1.5, 1.7, and 3.5 μM, respectively. The related base analoque, thymine-1-propenal, is a product of bleomycin-induced DNA strand-scission; the results of the present study bear on the mode of action of this antibiotic.