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

IMP Dehydrogenase: Structure, Mechanism, and Inhibition

“…These compounds display antineoplastic activity, which is reversed upon addition of guanosine, as commonly observed for IMPDH activity 198. However, this cytotoxicity is often more potent than IMPDH inhibition 196. The categorization of these compounds as IMPDH inhibitors awaits further confirmation.…”

“…Curiously, these compounds were reported to be competitive inhibitors with respect to IMP, though the data were not very convincing; given that the IMP binding site is conserved, the structural basis of this selectivity is not clear. The SAR around these compounds is also puzzling: the mechanism of very similar diones can vary from competitive versus IMP to competitive versus NAD + 196. The high values of K i , which require high concentrations of compound for inhibition, coupled with the broad nmr peaks 197, suggests that the active component may be a polymer or aggregate.…”

Synthesis of 3,5-Isoxazolidinediones and 1H-2,3-Benzoxazine-1,4(3H)-diones from Aliphatic Oximes and Dicarboxylic Acid Chlorides

“…General Procedure for the Reaction of Dialkylmalonyl Chlorides (6) with Oximes (7). To a solution of 25 mmol of oxime (7 or 12) and 75 mmol of Et 3 N in 70 mL of anhydrous Et 2 O at 0 °C was added dropwise over 15 min 25 mmol of dialkylmalonyl chloride (6).…”

“…The 3,5-isoxazolidinediones ( 1 ) are an important pharmacologically active class of compounds. We have shown that they are potent hypolipidemic 1 − 5 and cytotoxic 6 agents, specific inhibitors of the type-2 isoform of IMPDH, 7 and inhibitors of aldose reductase. 8 , 9 They also act as antidiabetic agents.…”

“…The 3,5-isoxazolidinediones ( 1 ) are an important pharmacologically active class of compounds. We have shown that they are potent hypolipidemic − and cytotoxic agents, specific inhibitors of the type-2 isoform of IMPDH, and inhibitors of aldose reductase. , They also act as antidiabetic agents. − Six-membered ring analogues of 1 include the 2 H -1,2-oxazine-3,6-diones ( 2 ) and the 1 H -2,3-benzoxazine-1,4­(3 H )-diones ( 3 ). − While there has been one report each on the fungicidal properties and the β-Lactamase pro-inhibitory activity of 3 , the pharmacological properties of 2 and 3 have been largely unexplored. In contrast, the corresponding 2 H -1,3-benzoxazine-2,4­(3 H )-diones ( 4 ) have a wide range of pharmacologic activities including antimycobacterial, − antituberculotic, − analgesic, , cardiovascular, antimitotic, antifungal, , cytotoxic, and antifungal, and the 2 H -1,4-benzoxazine-2,3­(4 H )­diones ( 5 ) are active as antimiotic, antimicrobial, antiallergic, , and renin inhibitory agents.…”