NEW ANTI-TUMOR IMIDAZOLE DERIVATIVE, 5-CARBAMOYL-H-1-IMIDAZOL-4-YL PIPERONYLATE, AS AN INHIBITOR OF PURINE SYNTHESIS AND ITS ACTIVATION BY ADENINE PHOSPHORIBOSYLTRANSFERASE
- 1 January 1982
- journal article
- research article
- Vol. 42 (3) , 1098-1102
Abstract
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 [mouse lymphocytic leukemia] was completely inhibited by 10-5 M SL-1250. This growth inhibition was significantly reversed in the presence of equimolar concentrations of guanine, guanosine or GMP to those of SL-1250. Hypoxanthine and xanthine were not effective. These effects of purine addition were observed to be quite similar in growth inhibition by SM-108. IMP dehydrogenase (EC 1.2.1.14) 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. 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 .times. 10-8 M. 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. Apparently, SL-1250 is, after being converted to SM-108, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and this SM-108 nucleotide blocks de novo synthesis of GMP by inhibiting IMP dehydrogenase.This publication has 0 references indexed in Scilit: