New antitumor imidazole derivative, 5-carbamoyl-1H-imidazol-4-yl piperonylate, as an inhibitor of purine synthesis and its activation by adenine phosphoribosyltransferase.
The mechanism of action of 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250), which has a broad antitumor spectrum, was examined by in vitro cell culture and enzymatic studies. In the serum-containing culture medium, SL-1250 was rapidly deacylated to 4-carbamoylimidazolium 5-olate (SM-108). Thus, SL-1250 might be acting on the cells in the form of SM-108. The growth of L5178Y cells was completely inhibited by 10(-5) M SL-1250. It should be noted that this growth inhibition was significantly reversed in the presence of equimolar concentrations of guanine, guanosine, or guanosine 5'-monophosphate to those of SL-1250. However, hypoxanthine and xanthine were not effective. These effects of purine addition were observed to be quite similar in growth inhibition by SM-108. It was found that inosine 5'-monophosphate dehydrogenase (EC 1.2.1.14; IMP dehydrogenase), a key enzyme of de novo purine synthesis, from Ehrlich carcinoma cells was inhibited by SM-108 only when 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and MgCl2 coexisted with SM-108. In contrast, a chemically synthetic ribonucleotide of SM-108 inhibited IMP dehydrogenase without PRPP and MgCl2, and the mode of inhibition was competitive with the Ki value of 2 x 10(-8) M. On the other hand, the inhibition of either growth of L5178Y cells or IMP dehydrogenase in the presence of PRPP and MgCl2 by these compounds was reversed by adenine. A nucleotide of SM-108 was chromatographically identified when [14C]SM-108 was incubated in the enzyme solution with PRPP and MgCl2. This conversion by enzyme was also inhibited by adenine. Viewed together, these results strongly suggest that SL-1250 is, after being converted to SM-108, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and that this SM-108 nucleotide blocks de novo synthesis of guanosine 5'-monophosphate by inhibiting IMP dehydrogenase.
D000228:Adenine Phosphoribosyltransferase / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D004789:Enzyme Activation; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000378:metabolism*; D007292:Inosine Nucleotides / Q000378:metabolism; D007940:Leukemia L5178 / Q000378:metabolism* / Q000473:pathology; D007942:Leukemia, Experimental / Q000378:metabolism*; D051379:Mice; D010430:Pentosyltransferases / Q000378:metabolism*; D011687:Purines / Q000096:biosynthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D007093:Imidazoles; D007292:Inosine Nucleotides; D011687:Purines; C028138:5-carbamoyl-1H-imidazol-4-yl-piperonylate; D007168:IMP Dehydrogenase; D010430:Pentosyltransferases; D000228:Adenine Phosphoribosyltransferase; C033758:4-carbamoylimidazolium 5-olate