Synthesis and Evaluation of Hydroxylated Polyamine Analogues as Antiproliferatives

A new means of accessing N -cyclopropylmethyl-N 11-ethylnorspermine (CPMENSPM) and the first synthesis of (2R,10S)-N 1-cyclopropylmethyl-2,10-dihydroxy-N 11-ethylnorspermine [(2R,10S)-(HO)2CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N 1,N 11-diethylnorspermine (DENSPM) or (2R,10R)-N 1,N 11-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)2DENSPM] after 96 h of treatment; the activity was comparable to that of (2S,10S)-N 1,N 11-diethyl-2,10-dihydroxynorspermine [(2S,10S)-(HO)2DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives. Only CPMENSPM, and not (2R,10S)-(HO)2CPMENSPM, lowered spermine pools. As with DENSPM and (2R,10R)-(HO)2DENSPM, both cyclopropyl analogues diminished ornithine decarboxylase and S-adenosylmethionine decarboxylase activity. Unlike the hydroxylated DENSPM compounds, both cyclopropyl norspermines substantially upregulated spermidine/spermine N 1-acetyltransferase. The most interesting effect of hydroxylating CPMENSPM is the profound reduction in toxicity compared with that of the parent drug. The same phenomenon had been observed for the DENSPM/(2R,10R)-(HO)2DENSPM pair. Thus, hydroxylation of norspermine analogues appears to be a way to maintain the compounds' antiproliferative activity while reducing their toxicity.