Tmolt4 leukemic type II isoform of IMP dehydrogenase as a target for 1,2,4-triazolidine-3,5-diones, 1-(1-(3-methylphenyl)ethylidineamino)-4,4-diethyl-3,5-azetidinediones, 3,5-isoxazolidinediones, and 4,4-disubstituted-3,5-pyrazolidinediones.
The 1,2,4-triazolidine-3,5-diones, 1-(1-(3-methylphenyl)ethylidineamino)-4,4-diethyl-3,5-azetidinediones, and 4,4-disubstituted-3,5-pyrazolidinediones proved to be potent competitive inhibitors of human Tmolt4 leukemia Type II IMP dehydrogenase [IMPDH] activity, an enzyme isoform which is induced in highly proliferating cells. On the other hand, the 3,5-isoxazolidinediones were shown to be uncompetitive inhibitors of Type II IMPDH activity. The correlation between inhibition of Type II IMPDH activity with the agents' ability to suppress DNA and purine syntheses in these Tmolt4 leukemia cell was positive. Type I IMPDH (i.e., the isoform that is present in normal cells) was not inhibited by these compounds suggesting that these agents would be less toxic to normal cells and have selective inhibition towards proliferating cells.
Hall
I H
IH
Division of Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7360, USA.
Barnes
B J
BJ
Ward
E S
ES
Wheaton
J R
JR
Warren
A E
AE
Izydore
R A
RA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D007168:IMP Dehydrogenase