Renau T E, Lee J S, Kim H, Young C G, Wotring L L, Townsend L B, Drach J C
Interdepartmental Graduate Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1078.
Biochem Pharmacol. 1994 Aug 17;48(4):801-7. doi: 10.1016/0006-2952(94)90059-0.
Non-nucleoside analogs of the pyrrolopyrimidine nucleosides toyocamycin, sangivamycin and thiosangivamycin have been synthesized and their cytotoxicity in mammalian cells determined. While studying the effects of 5-thioamide-substituted analogs on cell growth, we observed an interesting phenomenon in which cells recovered spontaneously from growth inhibition during extended incubations. HPLC studies demonstrated that the 5-thioamide moiety of several structurally dissimilar 7-substituted 4-aminopyrrolo[2,3-d]pyrimidines, including thiosangivamycin, is unstable in cell culture medium and is converted to the corresponding 5-nitrile with a half-life of approximately 48 h. In contrast, different substituents at the 4-position of the heterocycle significantly affected the stability of the 5-thioamide moiety. Conversion of the thioamide to the nitrile was caused by components in the cell culture medium, not components of serum. The above observations demonstrate that caution should be exercised in interpreting biological data obtained in vitro for 5-thioamide pyrrolo[2,3-d]pyrimidines.
已合成了吡咯并嘧啶核苷类抗生素丰加霉素、偏端霉素和硫偏端霉素的非核苷类似物，并测定了它们在哺乳动物细胞中的细胞毒性。在研究5-硫代酰胺取代类似物对细胞生长的影响时，我们观察到一个有趣的现象，即在延长培养期间，细胞会从生长抑制中自发恢复。高效液相色谱研究表明，几种结构不同的7-取代4-氨基吡咯并[2,3-d]嘧啶（包括硫偏端霉素）的5-硫代酰胺部分在细胞培养基中不稳定，会转化为相应的5-腈，半衰期约为48小时。相比之下，杂环4位上的不同取代基显著影响5-硫代酰胺部分的稳定性。硫代酰胺向腈的转化是由细胞培养基中的成分引起的，而非血清成分。上述观察结果表明，在解释体外获得的5-硫代酰胺吡咯并[2,3-d]嘧啶的生物学数据时应谨慎。
