INHIBITORS OF RIBONUCLEOTIDE REDUCTASE - COMPARATIVE EFFECTS OF AMINO-SUBSTITUTED AND HYDROXY-SUBSTITUTED PYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONES
INHIBITORS OF RIBONUCLEOTIDE REDUCTASE - COMPARATIVE EFFECTS OF AMINO-SUBSTITUTED AND HYDROXY-SUBSTITUTED PYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONES
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DOI：
10.1016/0006-2952(94)90105-8
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发表时间：
1994-07-19
影响因子：
5.8
通讯作者：
SARTORELLI, AC
中科院分区：
文献类型：
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作者：
CORY, JG;CORY, AH;SARTORELLI, AC
研究了一系列新的 α-(N)-杂环甲醛缩氨基硫脲 (HCT) 对 L1210 细胞培养生长、细胞周期转变、核酸生物合成和核糖核苷酸还原酶活性的影响。 3-氨基吡啶-2-甲醛缩氨基硫脲(3-AP)和3-氨基-4-甲基吡啶-2-甲醛缩氨基硫脲(3-AMP)是在抑制细胞生长和核糖核苷酸还原酶活性方面最具活性的测试化合物。 5-氨基吡啶-2-甲醛缩氨基硫脲(5-AP)和4-甲基-5-氨基吡啶-2-甲醛缩氨基硫脲(5-AMP)活性稍差。 3-AP、3-AMP、5-AP和5-AMP抑制[H-3]胸苷掺入DNA，但不影响[H-3]尿苷掺入RNA的速率。 3-AP 或 3-AMP 不会降低 [C-14] 胞苷分别摄取和掺入细胞核糖核苷酸和 RNA 的能力；然而，胞苷通过核糖核苷酸还原酶掺入DNA的过程受到显着抑制。因此，在3-AP和3-AMP处理的L1210细胞的酸溶部分中，放射性胞苷形成[C-14]脱氧核糖核苷酸的显着减少。与在相对较低浓度的 3-AP 和 3-AMP 下发生的 DNA 复制抑制一致，细胞在细胞周期的 S 期逐渐积累；在较高浓度的 3-AP 和 3-AMP 下，细胞周期 G(0)/G(1) 阶段的细胞积累速度更快，同时 8 期细胞群消失，这意味着 HCT 造成了第二个不太敏感的代谢损伤。 3-AMP 的 N-乙酰化导致化合物作为核糖核苷酸还原酶活性抑制剂的活性降低 10 倍，作为 L1210 细胞生长抑制剂的活性降低 8 倍。 5-AP 或 5-AMP 的 N-乙酰化不会改变这些化合物的抑制特性。获得的结果为进一步开发 HCT（特别是 3-AP 和 3-AMP）作为临床治疗癌症的潜在药物提供了实验依据。
A new series of alpha-(N)-heterocylic 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 sightly less active. 3-AP, 3-AMP, 5-AP and 5-AMP inhibited the incorporation of [H-3]thymidine into DNA without affecting the rate of incorporation of [H-3]uridine into RNA. The uptake and incorporation of [C-14]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 [C-14]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 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 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.