Inhibitors of ribonucleotide reductase. Comparative effects of amino- and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones.
A new series of alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazones (HCTs) was studied for their effects on L1210 cell growth in culture, cell cycle transit, nucleic acid biosynthesis and ribonucleotide reductase activity. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone (3-AMP) were the most active compounds tested with respect to inhibition of cell growth and ribonucleotide reductase activity. 5-Aminopyridine-2-carboxaldehyde thiosemicarbazone (5-AP) and 4-methyl-5-aminopyridine-2-carboxaldehyde thiosemicarbazone (5-AMP) were slightly less active. 3-AP, 3-AMP, 5-AP and 5-AMP inhibited the incorporation of [3H]thymidine into DNA without affecting the rate of incorporation of [3H]uridine into RNA. The uptake and incorporation of [14C]cytidine into cellular ribonucleotides and RNA, respectively, were not decreased by 3-AP or 3-AMP; however, the incorporation of cytidine into DNA via ribonucleotide reductase was inhibited markedly. Thus, a pronounced decrease in the formation of [14C]deoxyribonucleotides from radioactive cytidine occurred in the acid-soluble fraction of 3-AP- and 3-AMP-treated L1210 cells. Consistent with an inhibition of DNA replication that occurred at relatively low concentrations of 3-AP and 3-AMP, cells gradually accumulated in the S-phase of the cell cycle; at higher concentrations of 3-AP and 3-AMP, a more rapid accumulation of cells in the G0/G1 phase of the cell cycle occurred, with the loss of the S-phase population, implying that a second less sensitive metabolic lesion was created by the HCTs. N-Acetylation of 3-AMP resulted in a compound that was 10-fold less active as an inhibitor of ribonucleotide reductase activity and 8-fold less active as an inhibitor of L1210 cell growth. N-Acetylation of either 5-AP or 5-AMP did not alter the inhibitory properties of these compounds. The results obtained provide an experimental rationale for the further development of the HCTs, particularly 3-AP and 3-AMP, as potential drugs for clinical use in the treatment of cancer.
Cory
J G
JG
Department of Biochemistry, East Carolina University School of Medicine, Greenville, NC 27858.
Cory
A H
AH
Rappa
G
G
Lorico
A
A
Liu
M C
MC
Lin
T S
TS
Sartorelli
A C
AC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D007939:Leukemia L1210; D011725:Pyridines / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D011725:Pyridines; D013882:Thiosemicarbazones; C078156:5-hydroxy-4-methylpyridine-2-carboxaldehyde thiosemicarbazone; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C078158:3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone; C078155:3-hydroxy-4-methylpyridine-2-carboxaldehyde thiosemicarbazone; D004247:DNA; D012264:Ribonucleotide Reductases