SYNTHESIS AND EVALUATION OF UNSYMMETRICALLY SUBSTITUTED POLYAMINE ANALOGS AS MODULATORS OF HUMAN SPERMIDINE SPERMINE-N(1)-ACETYLTRANSFERASE(SSAT) AND AS POTENTIAL ANTITUMOR AGENTS

Spermidine/spermine-N1-acetyltransferase (SSAT),the rate-limiting step in polyamine catabolism, is critical for the interconversion and modu lation of cellular polyamines. Inhibitor-initiated induction of this e nzyme also appears to correlate with the sensitivity of tumor cells to a class of novel polyamine analogues, the bis(ethyl)polyamines. Thus, terminally alkylated polyamines which modulate the cellular level of SSAT could be of great value for understanding the role of this enzyme both in analogue-mediated cytotoxicity and in overall cellular polyam ine metabolism. Such analogues could also become important therapeutic agents by disrupting cellular polyamine metabolism. The structure-act ivity relationships defining the interaction of polyamine analogues wi th SSAT have not been fully elucidated, and, in particular, unsymmetri cally alkylated polyamines have not been synthesized and evaluated as modulators of SSAT. To this end, we now report the synthesis and preli minary biological evaluation of N1-ethyl-N-11-propargyl-4,8-diazaundec ane and ethyl-N-11-((cyclopropyl)methyl)-4,8-diazaundecane via a synth etic pathway which represents an efficient route to a variety of unsym metrically substituted polyamine analogues. The title compounds act as effective inhibitors of isolated human SSAT and produce a differentia l superinduction of SSAT in situ which appears to be associated with a cell specific cytotoxic response in two human lung cancer cell lines. In so doing, these analogues exhibit promising antitumor activity aga inst cultured human lung cancer cells.