Methylglyoxal bis(guanylhydrazone) analogs: multifunctional inhibitors for polyamine enzymes

Abstract

Methylglyoxal bis(3-aminopropyl-amidinohydrazone) (MGBA), methylglyoxal bis(4-aminobutyl-amidinohydrazone) (MGBT), methylglyoxal bis(cyclohexyl-amidinohydrazone) (MGBC) and methylglyoxal bis(butyl-amidinohydrazone) (MGBB) were synthesized as potent competitive inhibitors for polyamine biosynthetic enzymes. Four compounds competitively inhibited S-adenosylmethionine decarboxylase. Ornithine decarboxylase was also inhibited by MGBA, MGBT and BGBB competitively with ornithine. Furthermore, MGBC and MGBB inhibited spermidine synthase competitively with the substrate putrescine. All the compounds showed anti-proliferative effects on human leukemia Molt4B cells. The intracellular contents of putrescine, spermidine and spermine analyzed in MGBB-treated Molt4B cells, were shown to be depressed simultaneously. These results suggest that the combination of effective moieties in a single inhibitor molecule affecting different enzymic steps of the pathway would provide an efficient way to block the metabolic pathways.