Solution phase and solid phase synthesis of alkylated polyamine analogues as chemotherapeutic agents

The polyamines putrescine, spermidine and spermine are naturally occurring polycationic alkyl amines that have been demonstrated to be important in both normal and neoplastic cell growth, differentiation and in some cases survival. The polyamine pathway remains as an attractive target for chemotherapeutic interventions, since manipulation of cellular polyamine levels lead to a decrease in the rate of cell growth and in some instances lead to cytotoxicity.; N-alkylated analogues of the natural polyamines spermine, spermidine and putrescine exhibits strong cytotoxic activity against human tumor cell lines. It is well established that alphaN,o N-bisethyl derivatives of spermine and its higher and lower tetra amine homologues show promise as inhibitors of tumor cell proliferation.; We have developed synthetic routes both solid phase based and solution phase based that allow for the synthesis of a wide variety of polyamine analogues. Using these routes we have synthesized a number of alkyl polyamine analogues with enhanced antitumor activity compared to the parent molecule in the series, bis(ethyl)spermine. These analogues have been used further to develop structure activity relationships for the cytotoxic effects of alkyl polyamines and have also become valuable tools for determining the molecular mechanisms for analogue induced cytotoxicity. Also we have developed synthetic routs for the synthesis of the metabolically stable bis and mono alpha methylated and ethylated analogues.; As in the case of most anticancer drugs, for bisethyl tetra amines, their efficacious cytotoxic activity has to be balanced against their toxic side effects. Therefore the search for chemical variants of the bisethyl polyamine structures with broader therapeutic windows is being activity pursued.