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 cytotoxicity. 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 microM and 1.5, 1.7, and 3.5 microM, respectively. The related base analogue, 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.
Kalman
T I
TI
Department of Medicinal Chemistry, State University of New York, Buffalo 14260.
Marinelli
E R
ER
Xu
B
B
Reddy
A R
AR
Johnson
F
F
Grollman
A P
AP
D000171:Acrolein / Q000031:analogs & derivatives*; D000818:Animals; D001761:Bleomycin / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D003854:Deoxyribonucleotides / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000201:enzymology*; D051379:Mice; D008808:Mice, Inbred CBA; D011743:Pyrimidines / Q000494:pharmacology*; D013938:Thymidine Monophosphate / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003854:Deoxyribonucleotides; D011743:Pyrimidines; D001761:Bleomycin; D013938:Thymidine Monophosphate; D000171:Acrolein; D013940:Thymidylate Synthase