Jg. Cory et al., INHIBITORS OF RIBONUCLEOTIDE REDUCTASE - COMPARATIVE EFFECTS OF AMINO-SUBSTITUTED AND HYDROXY-SUBSTITUTED PYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONES, Biochemical pharmacology, 48(2), 1994, pp. 335-344
A new series of alpha-(N)-heterocylic carboxaldehyde thiosemicarbazone
s (HCTs) was studied for their effects on L1210 cell growth in culture
, cell cycle transit, nucleic acid biosynthesis and ribonucleotide red
uctase 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 inhibiti
on of cell growth and ribonucleotide reductase activity. 5-Aminopyridi
ne-2-carboxaldehyde thiosemicarbazone (5-AP) and 4-methyl-5-aminopyrid
ine-2-carboxaldehyde thiosemicarbazone (5-AMP) were sightly less activ
e. 3-AP, 3-AMP, 5-AP and 5-AMP inhibited the incorporation of [H-3]thy
midine into DNA without affecting the rate of incorporation of [H-3]ur
idine into RNA. The uptake and incorporation of [C-14]cytidine into ce
llular ribonucleotides and RNA, respectively, were not decreased by 3-
AP or 3-AMP; however, the incorporation of cytidine into DNA via ribon
ucleotide reductase was inhibited markedly. Thus, a pronounced decreas
e in the formation of [C-14]deoxyribonucleotides from radioactive cyti
dine occurred in the acid-soluble fraction of 3-AP- and 3-AMP-treated
L1210 cells. Consistent with an inhibition of DNA replication that occ
urred at relatively low concentrations of 3-AP and 3-AMP, cells gradua
lly accumulated in the S-phase of the cell cycle; at higher concentrat
ions of 3-AP and 3-AMP, a more rapid accumulation of cells in the G(0)
/G(1), phase of the cell cycle occurred, with the loss of the 8-phase
population, implying that a second less sensitive metabolic lesion was
created by the HCTs. N-Acetylation of 3-AMP resulted in a compound th
at 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 pr
operties of these compounds. The results obtained provide an experimen
tal 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.