BRANCHED-CHAIN AND UNSATURATED 1,7-DIAMINOHEPTANE DERIVATIVES AS DEOXYHYPUSINE SYNTHASE INHIBITORS

Deoxyhypusine synthase catalyzes the first step in the posttranslation al biosynthesis of the unusual amino acid hypusine [N-epsilon-(4-amino -2-hydroxybutyl)lysine] in eukaryotic translation initiation factor 5A (eIF-SA). eIF-SA and its single hypusine residue are essential for ce ll proliferation. Two series of 1,7-diaminoheptane derivatives were pr epared and tested as inhibitors of human deoxyhypusine synthase. These include branched-chain saturated derivatives and both branched- and s traight-chain unsaturated derivatives providing size and positional va riation in branching and different torsional constraints. Of the branc hed-chain compounds, 7-amino-1-guanidinooctane (39) proved to be the m ost potent inhibitor in vitro (IC50, 34 nM), while 1,7-diamino-trans-h ept-3-ene (20a) displayed the greatest inhibition (IC50, 0.7 mu M) amo ng the unsaturated compounds. Compound 39 also provided effective inhi bition of hypusine production in Chinese hamster ovary cells in cultur e. Considerations of the in vitro inhibition data reported here, along with earlier findings, allowed some speculation concerning the confor mation of the substrate spermidine during its productive interaction a t the active site of deoxyhypusine synthase. Published by Elsevier Sci ence Ltd.