Targeting of human Tmolt4 leukemic type II IMP dehydrogenase by cyclic imide related derivatives.
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 microM. 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 microM. 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.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7360, USA. iris_hall@unc.edu
Barnes
B J
BJ
Ward
E S
ES
Wheaton
J R
JR
Shaffer
K A
KA
Cho
S E
SE
Warren
A E
AE
D004273:DNA, Neoplasm / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007094:Imides / Q000138:chemical synthesis* / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis; D007942:Leukemia, Experimental / Q000201:enzymology*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007094:Imides; D007527:Isoenzymes; D007168:IMP Dehydrogenase