Synthesis and biological analysis of polyamine analogues

The polyamine biosynthetic and interconversion pathway has been viewed as an important chemotherapeutic target, since depletion of polyamines could result in the disruption of a variety of cellular functions, and may in specific cases lead to cytotoxicity. The inducible enzyme spermidine/spermine-N{dollar}sp1{dollar}-acetyltransferase (SSAT) is the first and rate limiting step in the catabolism of the natural polyamines, spermidine and spermine, in mammalian systems. It has recently been identified as an important target for the design of effective antitumor agents. We have recently synthesized and evaluated a series of alkyl-substituted polyamine analogues of general structure 1 which are cogeners of lead compounds that exhibit impressive antitumor activity (J. Med. Chem. 1993, 36, 2998-3004). An ongoing SAR study of these analogues has revealed that alkylpolyamines can produce potent antitumor, antiparasitic and/or apoptotic activity which is highly structure dependent. These relationships will provide us with valuable information as to the requirements for substrate binding and interaction with the SSAT catalytic site.; Two pentavalent phosphorus containing compounds, one phosphinate and one phosphonate analogue (Figure 2, general structure 2) were prepared as transition state analogue inhibitors of SSAT-mediated polyamine acetylation. These compounds act as potent inhibitors without superinduction of SSAT. A photoaffinity label (Figure 2, compound 13) was synthesized to identify a cell surface polyamine binding protein, which is thought to participate in polyamine transport. The characterization of this protein will provide valuable information concerning the mechanism and regulation of polyamine transport.; In this dissertation, the details of the preparation and preliminary biological evaluation of these compounds as antitumor and antiparasitic agents are reported.