2,3‐Dihydrophthalazine‐1,4‐diones, indazolones, 3‐imino‐1‐oxoisodolines, homophthalimides, napthalidimides, diphenamides, and 6,7‐dihydro‐5H‐dibenz[c,e]azepines proved to be potent inhibitors of the activity of human Tmolt4 T cell leukemia Type II IMP dehydrogenase (IMPDH). This inhibition was competitive, yielding Ki values in the range of 1.96 to 48.9 μM. The inhibition of Type II IMPDH correlated positively with the inhibition of the growth of Tmolt4 cells, the syntheses of DNA and purine, and the activity of crude IMPDH. The Type II IMPDH isoform is found in rapidly proliferating cells. The isoform present in normal resting cells, Type I IMPDH, was elevated by the compounds at 100 μM. In addition, Compound 5 significantly increased the Type I enzyme activity in a concentration and time dependent manner. The selectivity of these derivatives towards Type II IMPDH will allow for the separation of cellular effects, which should reduce clinical toxicity when treating with antimetabolite IMPDH inhibitors.

中文翻译：

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环酰亚胺相关衍生物靶向人 Tmolt4 白血病 II 型 IMP 脱氢酶

2,3-Dihydrophthalazine-1,4-diones、indazolones、3-imino-1-oxisodolines、homophthalimides、nathalidimides、diphenamides 和 6,7-dihydro-5H-dibenz[c,e]azepines 被证明是有效的抑制剂人 Tmolt4 T 细胞白血病 II 型 IMP 脱氢酶 (IMPDH) 的活性。这种抑制具有竞争性，产生的 Ki 值范围为 1.96 至 48.9 μM。II型IMPDH的抑制与Tmolt4细胞生长的抑制、DNA和嘌呤的合成以及粗IMPDH的活性呈正相关。II 型 IMPDH 同种型存在于快速增殖的细胞中。存在于正常静息细胞中的同工型 I 型 IMPDH 被 100 μM 的化合物升高。此外，化合物5以浓度和时间依赖性方式显着增加I型酶活性。