Specific multisubstrate adduct inhibitors of aminopropyltransferases and their effect on polyamine biosynthesis in cultured cells.

We have designed and synthesized multisubstrate adduct inhibitors for each of the three enzymes in the polyamine biosynthetic pathway (equation 1). The specific aminopropyltransferase inhibitors AdoDATO (2b) and AdoDATAD (2d) have been used to study the effects of specific polyamine depletion on cell growth. As shown in Table 2, these compounds effectively modulate the biosynthesis of Spd and Spm in vitro. However, tight regulation of the biosynthetic and degradative pathways results in little or no change in total polyamine levels in the presence of a single inhibitor (Table 2). Further studies with these aminopropyltransferase inhibitors in combination with other specific inhibitors of polyamine biosynthesis or degradation (e.g. DFMO) should shed light on the mechanism(s) underlying this tight biological regulation.