ACETYLASE TARGETED ANTINEOPLASTIC ANALOGUES

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The polyamine pathway is a logical target for chemotherapeutic intervention, since depletion of cellular polyamines leads to a decrease in rate of cell growth, and in some specific instances leads to cytotoxicity. A number of potent polyamine biosynthesis inhibitors have been developed as potential antitumor agents, but only one of these compounds has become a clinically useful agent. Thus, there is a continuing need for the design and synthesis of inhibitors of polyamine biosynthesis. The bis(ethyl)polyamines represent a novel class of polyamine analogues which exhibit promising antitumor effects in vitro and in vivo. Interestingly, the observed cytotoxic response appears to be tumor-type specific within the range of important human solid tumors. In responsive cell lines, cytotoxicity has been correlated to the propensity of the bis(ethyl)polyamines to induce the enzyme spermidine/spermine-N1- acetyltransferase (SSAT), the rate limiting step in the catabolism of polyamines, and to their ability to down-regulate cellular polyamine biosynthesis. The overall objectives of this proposal are to synthesize and examine the effects of a series of asymmetrically substituted polyamine analogues for potential use as antineoplastic agents, and as tools to facilitate an understanding of the mechanism of cell-type specific cytotoxicity demonstrated by some polyamine analogs. The proposed analogs are designed to act as reversible, irreversible, enzyme-activated or transition-state mimic-based inhibitors and/or inducers of SSAT, and the synthetic routes leading to the proposed analogues are of sufficient versatility to allow for selective functionalization to facilitate a structure/activity survey. Each analogue will be assayed for activity against purified human SSAT using a previously published assay procedure. Each analogue will be evaluated for potency and the ability to superinduce SSAT in an established lung tumor cell model system. Active analogues will also be used to determine the mechanism of tumor cell specific superinduction of SSAT, and as tools to determine the requirement of SSAT for cell-specific cytotoxicity. These studies should provide significant new information regarding the differences in polyamine metabolism exhibited between cell types, and could also provide a number of potentially important antineoplastic agents.