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Targeting of Human Tmolt4 Leukemic Type II IMP Dehydrogenase by Cyclic Imide Related Derivatives
Author(s) -
Hall Iris H.,
Barnes Betsy Jo,
Ward E. Stacy,
Wheaton Jessica R.,
Shaffer Kara A.,
Cho Sue E.,
Warren Amy E.
Publication year - 2001
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/1521-4184(200107)334:7<229::aid-ardp229>3.0.co;2-o
Subject(s) - chemistry , antimetabolite , enzyme , biochemistry , enzyme inhibitor , benzamide , imp dehydrogenase , de novo synthesis , isozyme , cell growth , cell culture , growth inhibition , purine , stereochemistry , toxicity , biology , transplantation , medicine , surgery , organic chemistry , mycophenolic acid , genetics
2,3‐Dihydrophthalazine‐1,4‐diones, indazolones, 3‐imino‐1‐oxoisodolines, homophthalimides, napthalidimides, diphenamides, and 6,7‐dihydro‐5 H ‐dibenz[ c,e ]azepines proved to be potent inhibitors of the activity of human Tmolt 4 T cell leukemia Type II IMP dehydrogenase (IMPDH). This inhibition was competitive, yielding K i 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 Tmolt 4 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.