Targeting of Human Tmolt4 Leukemic Type II IMP Dehydrogenase by Cyclic Imide Related Derivatives

Abstract

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.

The Cytotoxicity of Symmetrical and Unsymmetrical Bis(thiosemicarbazones) and Their Metal Complexes in Murine and Human Tumor Cells

“…The data suggest that the bis(thiosemicarbaoznes) interfered with nucleic acid metabolism as an anti-metabolite since DNA was not a target of the compounds under these conditions. This observation is quite different in that the copper(II) complexes of heterocyclic thiosemicarbazones cause DNA fragmentation and inhibited DNA topoisomerase II activity with no DNA-protein linked breaks [4][5][6][7] .…”

“…Heterocyclic N(4)-substituted thiosemicarbazones, N-(2)-pyridyl-N′-arylthioureas, and 2-substituted pyridine N-oxides and their copper(II) complexes have been shown to be potent antineoplastic agents, and cytotoxicity has been demonstrated against the growth of a number of murine and human tumor cells [1][2][3][4][5][6][7] . The 2-acetylpyridine N(4)-substituted thiosemicarbazones have demonstrated significant activity in the NCI screens for non-small cell lung cancer, breast cancer, and prostate cancer and leukemias [2].…”

“…Mode of action studies in L1210 lymphoid leukemia cells have demonstrated that these agents inhibit DNA and RNA syntheses at the enzymatic sites of IMP dehydrogenase, DNA polymerase α, ribonucleotide reductase, dihydrofolate reductase, nucleoside kinases, DNA topoisomerase II with DNA strand scission without DNA protein linked breaks [1][2][3][4][5][6] . The 2-formyl-, 2-acetyl-, and 2-benzoylpyridine N(4)-substituted thiosemicarbazones and their copper complexes demonstrated potent cytotoxic activity against the growth of human MCK-7 breast effusion, lung A549, and lung MB-9812, bone osteosarcoma Saos-2, and clear cell Caki renal tumor [7] . In Tmolt4 T cell leukemia cells these compounds inhibited the syntheses of DNA, RNA, and protein over 60 min at 25 to 100 µM.…”

4b,5,6,9-Tetrahydro-7H-dibenzo[c,e]pyrrolo[1,2-a]azepin-7-one

“…Dibenz[c,e]azepine derivatives attract the attention of synthetic and medicinal chemists due to their potential use in human and veterinary medicine. This scaffold is present in the vasodilator azapetine [1], as well as in a broad variety of compounds exhibiting anticancer [2][3][4][5][6][7][8], anti-inflammatory [9], hypolipidemic [10,11], and other types of biological activities [6,[12][13][14][15][16][17][18]. In addition, dibenz[c,e]azepines have been used as chiral organocatalysts in enantioselective synthesis [19,20].…”

Synthesis, characterization and X-ray crystal structures of the bis?ligand zinc(II) and cadmium(II) complexes of the methylpyruvate Schiff base of S-methyldithiocarbazate

“…Transition metal complexes of hard-soft nitrogen-sulfur chelating agents such as Schiff bases derived from S-alkyl-and S-aryl esters of dithiocarbazic acid [1][2][3][4][5][6][7][8][9][10][11][12][13] and thiosemicarbazones [14][15][16][17][18][19][20][21][22][23][24] have been the subject of considerable study because of their interesting physicochemical properties [25][26][27][28][29][30] and potentially useful chemotherapeutic activity [1,9,10,[17][18][19][20]24]. The methylpyruvate Schiff base of S-methyldithiocarbazate (Hmpsme; Figure 1a) has been found to exhibit promising anti-leukemia properties [31].…”